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1.  In vivo reprogramming of astrocytes to neuroblasts in the adult brain 
Nature cell biology  2013;15(10):10.1038/ncb2843.
Adult differentiated cells can be reprogrammed into pluripotent stem cells or lineage-restricted proliferating precursors in culture; however, this has not been demonstrated in vivo. Here, we show that the single transcription factor SOX2 is sufficient to reprogram resident astrocytes into proliferative neuroblasts in the adult mouse brain. These induced adult neuroblasts (iANBs) persist for months and can be generated even in aged brains. When supplied with BDNF and noggin or when the mice are treated with a histone deacetylase inhibitor, iANBs develop into electrophysiologically mature neurons, which functionally integrate into the local neural network. Our results demonstrate that adult astrocytes exhibit remarkable plasticity in vivo, a feature that might have important implications in regeneration of the central nervous system using endogenous patient-specific glial cells.
doi:10.1038/ncb2843
PMCID: PMC3867822  PMID: 24056302
3.  ISOFLURANE-INDUCED NEUROAPOPTOSIS IN THE NEONATAL RHESUS MACAQUE BRAIN 
Anesthesiology  2010;112(4):834-841.
Background
Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of nonhuman primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathological changes.
Method
With the same intensity of physiological monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end tidal Vol% (endotracheally intubated, mechanically ventilated), and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons.
Results
Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0 to 48.2) apoptotic cells per mm3 of brain tissue in the isoflurane group and only 2.5 (range, 1.9 to 3.8) in the control group (difference significant at p = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions.
Conclusion
The developing nonhuman primate brain is sensitive to the apoptogenic action of isoflurane, and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.
doi:10.1097/ALN.0b013e3181d049cd
PMCID: PMC3962067  PMID: 20234312
4.  Unifying Viral Genetics and Human Transportation Data to Predict the Global Transmission Dynamics of Human Influenza H3N2 
PLoS Pathogens  2014;10(2):e1003932.
Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evolutionary analyses of pathogen genome sequences increasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largely neglected the wealth of information on human mobility, mainly because no statistical framework exists within which viral gene sequences and empirical data on host movement can be combined. Here, we address this problem by applying a phylogeographic approach to elucidate the global spread of human influenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A viruses worldwide. Using a framework that estimates the migration history of human influenza while simultaneously testing and quantifying a range of potential predictive variables of spatial spread, we show that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more local scales spread is also determined by processes that correlate with geographic distance. Our analyses further confirm a central role for mainland China and Southeast Asia in maintaining a source population for global influenza diversity. By comparing model output with the known pandemic expansion of H1N1 during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data on human mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza viruses are best explained by combining human mobility data with the spatial information inherent in sampled viral genomes. The integrated approach introduced here offers great potential for epidemiological surveillance through phylogeographic reconstructions and for improving predictive models of disease control.
Author Summary
What explains the geographic dispersal of emerging pathogens? Reconstructions of evolutionary history from pathogen gene sequences offer qualitative descriptions of spatial spread, but current approaches are poorly equipped to formally test and quantify the contribution of different potential explanatory factors, such as human mobility and demography. Here, we use a novel phylogeographic method to evaluate multiple potential predictors of viral spread in human influenza dynamics. We identify air travel as the predominant driver of global influenza migration, whilst also revealing the contribution of other mobility processes at more local scales. We demonstrate the power of our inter-disciplinary approach by using it to predict the global pandemic expansion of H1N1 influenza in 2009. Our study highlights the importance of integrating evolutionary and ecological information when studying the dynamics of infectious disease.
doi:10.1371/journal.ppat.1003932
PMCID: PMC3930559  PMID: 24586153
5.  Integrating influenza antigenic dynamics with molecular evolution 
eLife  2014;3:e01914.
Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution.
DOI: http://dx.doi.org/10.7554/eLife.01914.001
eLife digest
Every year, seasonal influenza, commonly called flu, infects up to one in five people around the world, and causes up to half a million deaths. Even though the human immune system can detect and destroy the virus that causes influenza, people can catch flu many times throughout their lifetimes because the virus keeps evolving in an effort to avoid the immune system. This antigenic drift—so-called because the antigens displayed by the virus keep changing—also explains why influenza vaccines become less effective over time and need to be reformulated every year.
It is possible to determine which antigens are displayed by a new strain of the virus by observing how blood samples that respond to known strains respond to the new strain. This information about the “antigenic phenotype” of the virus can be plotted on an antigenic map in which strains with similar antigens cluster together. Gene sequencing has shown that there are four subtypes of the flu virus that commonly infect people; but the relationship between changes in antigenic phenotype and changes in gene sequences of the influenza virus is poorly understood.
Bedford et al. have now developed an approach to combine antigenic maps with genetic information about the four subtypes of the human flu virus. This revealed that the antigenic phenotype of H3N2—a subtype that is becoming increasingly common—evolved faster than the other three subtypes. Further, a correlation was observed between antigenic drift and the number of new influenza cases per year for each flu strain. This suggests that knowing which antigenic phenotypes are present at the start of flu season could help predict which strains of the virus will predominate later on.
The work of Bedford et al. provides a useful framework to study influenza, and could help to pinpoint which changes in viral genes cause the changes in antigens. This information could potentially speed up the development of new flu vaccines for each flu season.
DOI: http://dx.doi.org/10.7554/eLife.01914.002
doi:10.7554/eLife.01914
PMCID: PMC3909918  PMID: 24497547
influenza; evolution; antigenic cartography; phylogenetics; Bayesian inference; multidimensional scaling; viruses
6.  The application of multiple reaction monitoring and multi-analyte profiling to HDL proteins 
Background
HDL carries a rich protein cargo and examining HDL protein composition promises to improve our understanding of its functions. Conventional mass spectrometry methods can be lengthy and difficult to extend to large populations. In addition, without prior enrichment of the sample, the ability of these methods to detect low abundance proteins is limited. Our objective was to develop a high-throughput approach to examine HDL protein composition applicable to diabetes and cardiovascular disease (CVD).
Methods
We optimized two multiplexed assays to examine HDL proteins using a quantitative immunoassay (Multi-Analyte Profiling- MAP) and mass spectrometric-based quantitative proteomics (Multiple Reaction Monitoring-MRM). We screened HDL proteins using human xMAP (90 protein panel) and MRM (56 protein panel). We extended the application of these two methods to HDL isolated from a group of participants with diabetes and prior cardiovascular events and a group of non-diabetic controls.
Results
We were able to quantitate 69 HDL proteins using MAP and 32 proteins using MRM. For several common proteins, the use of MRM and MAP was highly correlated (p < 0.01). Using MAP, several low abundance proteins implicated in atherosclerosis and inflammation were found on HDL. On the other hand, MRM allowed the examination of several HDL proteins not available by MAP.
Conclusions
MAP and MRM offer a sensitive and high-throughput approach to examine changes in HDL proteins in diabetes and CVD. This approach can be used to measure the presented HDL proteins in large clinical studies.
doi:10.1186/1476-511X-13-8
PMCID: PMC3900256  PMID: 24397693
High density lipoprotein; Proteomics; Multiple reaction monitoring; Multi-analyte panel; Diabetes; Cardiovascular disease
7.  Draft Genome Sequence of the Antibiotic-Producing Epiphytic Isolate Pantoea ananatis BRT175 
Genome Announcements  2013;1(6):e00902-13.
Pantoea is a member of the Enterobacteriaceae, whose members have been shown to produce novel antibiotics. Here, we report the 4.8-Mb genome sequence of Pantoea ananatis strain BRT175, an epiphytic isolate from strawberries that produces an antibiotic that is effective against the fire blight pathogen, Erwinia amylovora.
doi:10.1128/genomeA.00902-13
PMCID: PMC3820774  PMID: 24201193
8.  Draft Genome Sequence of the Antibiotic-Producing Cystic Fibrosis Isolate Pantoea agglomerans Tx10 
Genome Announcements  2013;1(5):e00904-13.
Pantoea agglomerans is an enteric bacterium that is capable of causing both plant and human disease. Here, we report the genome sequence of a cystic fibrosis isolate, P. agglomerans Tx10, which produces an antibiotic that is effective against Staphylococcus aureus.
doi:10.1128/genomeA.00904-13
PMCID: PMC3814576  PMID: 24179115
9.  Quantifying the Impact of Immune Escape on Transmission Dynamics of Influenza 
Science (New York, N.Y.)  2009;326(5953):726-728.
Influenza virus evades prevailing natural and vaccine-induced immunity by accumulating antigenic change in the haemagglutinin surface protein. Linking amino acid substitutions in haemagglutinin epitopes to epidemiology has been problematic because of the scarcity of data connecting these scales. We use experiments on equine influenza virus to address this issue, quantifying how key parameters of viral establishment and shedding increase the probability of transmission with genetic distance between previously immunizing virus and challenge virus. Qualitatively similar patterns emerge from analyses based on antigenic distance and from a published human influenza study. Combination of the equine data and epidemiological models allows us to calculate the effective reproductive number of transmission as a function of relevant genetic change in the virus, illuminating the probability of influenza epidemics as a function of immunity.
doi:10.1126/science.1175980
PMCID: PMC3800096  PMID: 19900931
10.  Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution 
The Journal of General Virology  2012;93(Pt 9):1996-2007.
Each year, influenza viruses cause epidemics by evading pre-existing humoral immunity through mutations in the major glycoproteins: the haemagglutinin (HA) and the neuraminidase (NA). In 2004, the antigenic evolution of HA of human influenza A (H3N2) viruses was mapped (Smith et al., Science 305, 371–376, 2004) from its introduction in humans in 1968 until 2003. The current study focused on the genetic evolution of NA and compared it with HA using the dataset of Smith and colleagues, updated to the epidemic of the 2009/2010 season. Phylogenetic trees and genetic maps were constructed to visualize the genetic evolution of NA and HA. The results revealed multiple reassortment events over the years. Overall rates of evolutionary change were lower for NA than for HA1 at the nucleotide level. Selection pressures were estimated, revealing an abundance of negatively selected sites and sparse positively selected sites. The differences found between the evolution of NA and HA1 warrant further analysis of the evolution of NA at the phenotypic level, as has been done previously for HA.
doi:10.1099/vir.0.043059-0
PMCID: PMC3542130  PMID: 22718569
11.  Musculoskeletal disorders and symptom severity among Australian dental hygienists 
BMC Research Notes  2013;6:250.
Background
Recent literature has identified that musculoskeletal disorders (MSD) are a significant occupational health issue for both dentists and dental hygienists. Research on the occupational health of dental hygienists is lacking in Australia, which is of particular concern given that it is a rapidly growing field in this country. The aims of this research are to investigate the prevalence of MSD and correlating regions of pain among Australian dental hygienists. A self-reporting questionnaire was distributed to all registered dental hygienists in Australia. The questionnaire was a modified version of a validated tool, used previously among health practitioners and students.
Results
A total of 624 dental hygienists responded to the questionnaire, achieving a response rate of 42%. MSD were frequently reported by dental hygienists in the neck (85%), shoulder (70%), and lower back (68%). Of those reporting pain, over two thirds reported that the pain lasted for longer than two days, for all body regions. Logistic regression analysis revealed that there is a correlation between reports of MSD in the neck, shoulder and lower back regions.
Conclusions
Overall, this study suggests that MSD are a reasonably common problem for Australian dental hygienists, and that they often need to seek medical treatment for these problems. It is concerning that there is a correlation between reports of MSD in the neck, shoulder and lower back regions; further studies are needed to establish the epidemiological patterns of MSD in this profession.
doi:10.1186/1756-0500-6-250
PMCID: PMC3704656  PMID: 23822098
Musculoskeletal disorders; Dental hygienist; Occupational health
12.  Identification of two small regulatory RNAs linked to virulence in Brucella abortus 2308 
Molecular Microbiology  2012;85(2):345-360.
Summary
Hfq is an RNA-binding protein that functions in post-transcriptional gene regulation by mediating interactions between mRNAs and small regulatory RNAs (sRNAs). Two proteins encoded by BAB1_1794 and BAB2_0612 are highly overproduced in a Brucella abortus hfq mutant compared to the parental strain, and recently, expression of orthologs of these proteins in Agrobacterium tumefaciens was shown to be regulated by two sRNAs, called AbcR1 and AbcR2. Orthologous sRNAs (likewise designated AbcR1 and AbcR2) have been identified in B. abortus 2308. In Brucella, abcR1 and abcR2 single mutants are not defective in their ability to survive in cultured murine macrophages, but an abcR1 abcR2 Sdouble mutant exhibits significant attenuation in macrophages. Additionally, the abcR1 abcR2 double mutant displays significant attenuation in a mouse model of chronic Brucella infection. Quantitative proteomics and microarray analyses revealed that the AbcR sRNAs predominantly regulate genes predicted to be involved in amino acid and polyamine transport and metabolism, and Northern blot analyses indicate that the AbcR sRNAs accelerate the degradation of the target mRNAs. In an E. coli two-plasmid reporter system, over-expression of either AbcR1 or AbcR2 was sufficient for regulation of target mRNAs, indicating that the AbcR sRNAs from Brucella abortus 2308 perform redundant regulatory functions.
doi:10.1111/j.1365-2958.2012.08117.x
PMCID: PMC3391331  PMID: 22690807
13.  A review of Influenza haemagglutinin receptor binding as it relates to pandemic properties 
Vaccine  2012;30(29):4369-4376.
Haemagglutinin is a determinant of many viral properties, and successful adaptation to a human-like form is thought to be an important step toward pandemic influenza emergence. The availability of structurally distinct sialic acid linked receptors in the sites of human and avian influenza infection are generally held to account for the differences observed, but the relevance of other selection pressures has not been elucidated. There is evidence for genetic and structural constraints of haemagglutinin playing a role in restricting haemagglutinin adaptation, and also for differences in the selection pressure to alter binding, specifically when considering virus replication within host compared to transmission between hosts. Understanding which characteristics underlie such adaptations in humans is now possible in greater detail by using glycan arrays. However, results from these assays must also interpreted in context of an as yet still to be determined detailed knowledge of the structural diversity of sialic acids in the human respiratory tract. A clearer understanding of the evolutionary benefits conveyed by different haemagglutinin properties would have substantial impact and would affect the risk we allocate to viral propagation in different species, such as swine and poultry. Relevant to the H5N1 threat, current evidence also suggests that mortality associated with any emergent pandemic from current strains may be reduced if haemagglutinin specificity changes, further emphasising the importance of understanding how and if selection pressures in the human will cause such an alteration.
doi:10.1016/j.vaccine.2012.02.076
PMCID: PMC3372863  PMID: 22682293
14.  Computational Biomarker Pipeline from Discovery to Clinical Implementation: Plasma Proteomic Biomarkers for Cardiac Transplantation 
PLoS Computational Biology  2013;9(4):e1002963.
Recent technical advances in the field of quantitative proteomics have stimulated a large number of biomarker discovery studies of various diseases, providing avenues for new treatments and diagnostics. However, inherent challenges have limited the successful translation of candidate biomarkers into clinical use, thus highlighting the need for a robust analytical methodology to transition from biomarker discovery to clinical implementation. We have developed an end-to-end computational proteomic pipeline for biomarkers studies. At the discovery stage, the pipeline emphasizes different aspects of experimental design, appropriate statistical methodologies, and quality assessment of results. At the validation stage, the pipeline focuses on the migration of the results to a platform appropriate for external validation, and the development of a classifier score based on corroborated protein biomarkers. At the last stage towards clinical implementation, the main aims are to develop and validate an assay suitable for clinical deployment, and to calibrate the biomarker classifier using the developed assay. The proposed pipeline was applied to a biomarker study in cardiac transplantation aimed at developing a minimally invasive clinical test to monitor acute rejection. Starting with an untargeted screening of the human plasma proteome, five candidate biomarker proteins were identified. Rejection-regulated proteins reflect cellular and humoral immune responses, acute phase inflammatory pathways, and lipid metabolism biological processes. A multiplex multiple reaction monitoring mass-spectrometry (MRM-MS) assay was developed for the five candidate biomarkers and validated by enzyme-linked immune-sorbent (ELISA) and immunonephelometric assays (INA). A classifier score based on corroborated proteins demonstrated that the developed MRM-MS assay provides an appropriate methodology for an external validation, which is still in progress. Plasma proteomic biomarkers of acute cardiac rejection may offer a relevant post-transplant monitoring tool to effectively guide clinical care. The proposed computational pipeline is highly applicable to a wide range of biomarker proteomic studies.
Author Summary
Novel proteomic technology has led to the generation of vast amounts of biological data and the identification of numerous potential biomarkers. However, computational approaches to translate this information into knowledge capable of impacting clinical care have been lagging. We propose a computational proteomic pipeline for biomarker studies that is founded on the combination of advanced statistical methodologies. We demonstrate our approach through the analysis of data obtained from heart transplant patients. Heart transplantation is the gold standard treatment for patients with end-stage heart failure, but is complicated by episodes of immune rejection that can adversely impact patient outcomes. Current rejection monitoring approaches are highly invasive, requiring a biopsy of the heart. This work aims to reduce the need for biopsies, and demonstrate the power and utility of computational approaches in proteomic biomarker discovery. Our work utilizes novel high-throughput proteomic technology combined with advanced statistical techniques to identify blood markers that guide the decision as to whether a biopsy is warranted, reduce the number of unnecessary biopsies, and ultimately diagnose the presence of rejection in heart transplant patients. Additionally, the proposed computational methodologies can be applied to a range of proteomic biomarker studies of various diseases and conditions.
doi:10.1371/journal.pcbi.1002963
PMCID: PMC3617196  PMID: 23592955
15.  Avian Influenza Virus Surveillance in Wild Birds in Georgia: 2009–2011 
PLoS ONE  2013;8(3):e58534.
The Caucasus, at the border of Europe and Asia, is important for migration and over-wintering of wild waterbirds. Three flyways, the Central Asian, East Africa-West Asia, and Mediterranean/Black Sea flyways, converge in the Caucasus region. Thus, the Caucasus region might act as a migratory bridge for influenza virus transmission when birds aggregate in high concentrations in the post-breeding, migrating and overwintering periods. Since August 2009, we have established a surveillance network for influenza viruses in wild birds, using five sample areas geographically spread throughout suitable habitats in both eastern and western Georgia. We took paired tracheal and cloacal swabs and fresh feces samples. We collected 8343 swabs from 76 species belonging to 17 families in 11 orders of birds, of which 84 were real-time RT-PCR positive for avian influenza virus (AIV). No highly pathogenic AIV (HPAIV) H5 or H7 viruses were detected. The overall AIV prevalence was 1.6%. We observed peak prevalence in large gulls during the autumn migration (5.3–9.8%), but peak prevalence in Black-headed Gulls in spring (4.2–13%). In ducks, we observed increased AIV prevalence during the autumn post-moult aggregations and migration stop-over period (6.3%) but at lower levels to those observed in other more northerly post-moult areas in Eurasia. We observed another prevalence peak in the overwintering period (0.14–5.9%). Serological and virological monitoring of a breeding colony of Armenian Gulls showed that adult birds were seropositive on arrival at the breeding colony, but juveniles remained serologically and virologically negative for AIV throughout their time on the breeding grounds, in contrast to gull AIV data from other geographic regions. We show that close phylogenetic relatives of viruses isolated in Georgia are sourced from a wide geographic area throughout Western and Central Eurasia, and from areas that are represented by multiple different flyways, likely linking different host sub-populations.
doi:10.1371/journal.pone.0058534
PMCID: PMC3596303  PMID: 23516501
16.  Influenza Vaccination Uptake among the Working Age Population of Japan: Results from a National Cross-Sectional Survey 
PLoS ONE  2013;8(3):e59272.
Background
Influenza vaccination rates among Japanese people of working age (20–69 years) is currently suboptimal, and the reasons for this have not been clearly elucidated. This study examined factors associated with vaccination intention among the working age population in Japan during September 2011, one-month prior to influenza vaccination becoming available.
Methodology/Principal Findings
A web-based survey of intention to be vaccinated against influenza in the coming season was undertaken among 3,129 Japanese aged 20 to 69 years. Multinomial logistic regression analysis was used to explore the associations between vaccination intent and other variables. Influenza vaccination intent was associated with having been vaccinated in the previous year (Odds Ratio (OR): 3.81; 95% Confidence Interval (CI): 3.75–3.86), the number of children per household (one compared with zero; OR: 1.37; 95%CI: 1.11–1.65), and household income ($50,000 to <$100,000 compared with $0 to <$50,000; OR: 1.30; 95%CI: 1.07–1.54). Smoking was inversely associated with influenza vaccine uptake (current smokers compared with non-smokers; OR: 0.79; 95%CI: 0.61–0.98). A history of either the survey respondent or a household member having being medically diagnosed with influenza in the previous year was not statistically associated with future influenza vaccination intent.
Conclusions/Significance
Overall, this suggests that intention to be vaccinated among working age Japanese is associated with a past history of influenza vaccination, having children, and the household's income. As such, consideration of these factors should now form the cornerstone of strategies to encourage increased uptake of vaccination against influenza in future years.
doi:10.1371/journal.pone.0059272
PMCID: PMC3595249  PMID: 23555010
17.  KETAMINE-INDUCED NEUROAPOPTOSIS IN THE FETAL AND NEONATAL RHESUS MACAQUE BRAIN 
Anesthesiology  2012;116(2):372-384.
Background
Exposure of rhesus macaque fetuses for 24 h, or neonates for 9 h, to ketamine anesthesia causes neuroapoptosis in the developing brain. The present study further clarifies the minimum exposure required for, and the extent and spatial distribution of, ketamine-induced neuroapoptosis in rhesus fetuses and neonates.
Method
Ketamine was administered by intravenous infusion for 5 h to postnatal day 6 rhesus neonates, or to pregnant rhesus females at 120 days gestation (full term = 165 days). Three hours later, fetuses were delivered by caesarian section, and the fetal and neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by activated caspase-3 staining.
Results
Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant increase in apoptotic profiles compared to drug-naive controls (fetal n = 4; neonatal n = 5). Loss of neurons due to ketamine exposure was 2.2 times greater in fetuses than in neonates. The pattern of neurodegeneration in fetuses was different from that in neonates, and all subjects exposed at either age had a pattern characteristic for that age.
Conclusion
The developing rhesus macaque brain is sensitive to the apoptogenic action of ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce a significant neuroapoptosis response at either age. The pattern of neurodegeneration induced by ketamine in fetuses was different from that in neonates, and loss of neurons attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
doi:10.1097/ALN.0b013e318242b2cd
PMCID: PMC3433282  PMID: 22222480
18.  Declining Rates of Tobacco Use in the Japanese Medical Profession, 1965–2009 
Journal of Epidemiology  2013;23(1):4-11.
Background
Although there has been a downward trend in smoking rates among medical doctors in recent years, rates have been higher among Japanese doctors when compared internationally.
Methods
We extensively reviewed all published English- and Japanese-language articles that reported the smoking rates of Japanese doctors.
Results
A total of 36 articles were examined, most of which had been conducted as postal surveys, usually by a national, prefectural, or local medical association. Sample sizes ranged from 17 to 11 773, and response rates ranged from 33% to 91%. National surveys conducted between 1965 and 2009 suggest that there has been a statistically significant (P < 0.0001) decline in smoking rates among Japanese doctors (from around 68% to 16% among males and from 19% to 5% among females).
Conclusions
Overall, the published data reveal a significant decline in smoking rates among Japanese doctors since 1965, especially among men. Although less than one-fifth of Japanese male doctors now smoke, more work needs to be done in tobacco control to help further reduce the burden of smoking, especially in medical schools.
doi:10.2188/jea.JE20120121
PMCID: PMC3700230  PMID: 23149752
smoking; tobacco; physician; doctor; Japan
19.  Wearing face masks in public during the influenza season may reflect other positive hygiene practices in Japan 
BMC Public Health  2012;12:1065.
Background
Although the wearing of face masks in public has not been recommended for preventing influenza, these devices are often worn in many Asian countries during the influenza season. In Japan, it is thought that such behavior may be an indicator of other positive hygiene practices. The aim of this study, therefore, was to determine if wearing a face mask in public is associated with other positive hygiene practices and health behaviors among Japanese adults.
Methods
We initially recruited around 3,000 Japanese individuals ranging from 20 to 69 years of age who were registered with a web survey company. Participants were asked to recall their personal hygiene practices during the influenza season of the previous year. Logistic regression analysis was then used to examine the associations between wearing a face mask in public and personal hygiene practices and health behaviors.
Results
A total of 3,129 persons responded to the survey, among whom 38% reported that they had worn a face mask in public during the previous influenza season. Wearing a face mask in public was associated with various self-reported hygiene practices including: frequent hand washing (adjusted Odds Ratio [OR]: 1.67; 95% Confidence Interval [95%CI]: 1.34-1.96), occasional hand washing (OR: 1.43; 95%CI: 1.10-1.75), frequently avoiding crowds (OR: 1.85; 95%CI: 1.70-1.98), occasionally avoiding crowds (OR: 1.65; 95%CI: 1.53-1.76), frequent gargling (OR: 1.68; 95%CI: 1.51-1.84), occasional gargling (OR: 1.46; 95%CI: 1.29-1.62), regularly avoiding close contact with an infected person (OR: 1.50; 95%CI: 1.33-1.67), occasionally avoiding close contact with an infected person (OR: 1.31; 95%CI: 1.16-1.46), and being vaccinated of influenza in the last season (OR: 1.31; 95%CI: 1.17-1.45).
Conclusions
Overall, this study suggests that wearing a face mask in public may be associated with other personal hygiene practices and health behaviors among Japanese adults. Rather than preventing influenza itself, face mask use might instead be a marker of additional, positive hygiene practices and other favorable health behaviors in the same individuals.
doi:10.1186/1471-2458-12-1065
PMCID: PMC3536629  PMID: 23227885
Face mask; Health behavior; Hygiene practices; Influenza
20.  A tale of two soles: sociomechanical and biomechanical considerations in diabetic limb salvage and amputation decision-making in the worst of times 
Diabetic Foot & Ankle  2012;3:10.3402/dfa.v3i0.18633.
Foot ulcerations complicated by infection are the major cause of limb loss in people with diabetes. This is especially true in those patients with severe sepsis. Determining whether to amputate or attempt to salvage a limb often requires in depth evaluation of each individual patient's physical, mental, and socioeconomic status. The current report presents and juxtaposes two similar patients, admitted to the same service at the same time with severe diabetic foot infections complicated by sepsis. We describe in detail the similarities and differences in the clinical presentation, extent of infection, etiology, and socioeconomic concerns that ultimately led to divergent clinical decisions regarding the choices of attempting diabetic limb salvage versus primary amputation and prompt rehabilitation.
doi:10.3402/dfa.v3i0.18633
PMCID: PMC3464045  PMID: 23050063
diabetic foot; Charcot arthropathy; diabetic limb salvage; diabetic foot infection; amputation
21.  Tobacco smoking among doctors in mainland China: a study from Shandong province and review of the literature 
Tobacco Induced Diseases  2012;10(1):14.
Background
Tobacco control represents a key area in which doctors can make a significant positive impact on their patients’ lives. Despite this fact, however, doctors in certain regions of China are known to smoke tobacco at rates similar to or even exceeding those seen within the general population.
Objective
This study sought to investigate the smoking habits of doctors at a teaching hospital in Shandong province, as well as providing a brief review of smoking research that has been conducted among doctors elsewhere in China.
Method
An anonymous questionnaire survey was distributed to doctors working at a university teaching hospital in 2008, as part of a larger study of occupational health issues in the healthcare profession.
Results
The overall smoking prevalence rate of doctors in this study was 36.3% with significant differences observed between the genders (males: 46.7% and females: 5.3%). Age and total career length were also correlated with smoking habit, although no significant associations were found with department of employment.
Conclusions
Overall, our study suggests that smoking rates among doctors in Shandong province are higher than those documented in many other countries, a finding which is consistent with previous research conducted in some other Chinese provinces. Addressing this issue from an intrinsic cultural perspective will clearly need to form the cornerstone of tobacco control efforts within the Chinese medical community in future years.
doi:10.1186/1617-9625-10-14
PMCID: PMC3519549  PMID: 23006640
China; Chinese; Doctor; Physician; Smoking; Tobacco; Medical
22.  Background, Expectations and Beliefs of a Chiropractic Student Population: A Cross-Sectional Survey 
Purpose: Research encompassing the characteristics of chiropractic students is limited. The purpose of our study was to evaluate a current chiropractic student population enrolled at a chiropractic college concerning demographics, expectations, and beliefs. Methods: A 44-item survey was administered to volunteer participants. Direct verbal interaction in a classroom setting to potential participants was the recruitment strategy used. Data were collected and stored on a safe network. Percentages for all responses were calculated and means were recorded where appropriate. Results: A total of 664 students participated of 877 potential eligible candidates (75%). The respondents tended to be 21–25 years of age, Caucasian, and male. Most respondents expected to work in a private practice immediately following graduation and anticipated an annual income of at least $100,000 eventually. Respondents preferred the retaining of the term, “subluxation,” and identified the importance of new and emerging scientific data. Additionally, respondents held the viewpoint that some non-musculoskeletal diseases can be treated effectively with spinal manipulation as a primary treatment. Conclusions: The majority of chiropractic students in our study were represented by specific demographic characteristics, and a strong favoritism toward the expectations of working in a private practice setting and earning at least $100,000 per year at some point in their career. Distinct beliefs are shared between chiropractic students and practicing chiropractors in North America, and certain aspects of students in our study are comparable to chiropractic students in similar studies.
doi:10.7899/JCE-11-031
PMCID: PMC3557650  PMID: 23362362
Attitude; Chiropractic; Cross Sectional Survey; Education; Students
23.  The potential for respiratory droplet transmissible A/H5N1 influenza virus to evolve in a mammalian host 
Science (New York, N.Y.)  2012;336(6088):1541-1547.
Avian A/H5N1 influenza viruses pose a pandemic threat. As few as five amino acid substitutions, or four with reassortment, might be sufficient for mammal-to-mammal transmission by respiratory droplets. From surveillance data we find that two of these substitutions are common in A/H5N1 viruses and thus some viruses might require only three additional substitutions to become transmissible via respiratory droplets between mammals. We use a mathematical model of within-host virus evolution to study factors that could increase and decrease the probability of the remaining substitutions evolving after the virus has infected a mammalian host. These factors combined with the presence of some of these substitutions in circulating strains, make a virus evolving in nature a potentially serious threat. These results highlight critical areas where more data are needed for assessing, and potentially averting, this threat.
doi:10.1126/science.1222526
PMCID: PMC3426314  PMID: 22723414
24.  Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis 
Neurobiology of disease  2011;43(2):356-363.
Glucocorticoids are used to treat respiratory dysfunction associated with premature birth but have been shown to cause neurodevelopmental deficits when used therapeutically. Recently, we established that acute glucocorticoid exposure at clinically relevant doses produces neural progenitor cell apoptosis in the external granule layer of the developing mouse cerebellum and permanent decreases in the number of cerebellar neurons. As the cerebellum naturally matures and neurogenesis is no longer needed, the external granule layer decreases proliferation and permanently disappears during the second week of life. At this same time, corticosterone (the endogenous rodent glucocorticoid) release increases and a glucocorticoid-metabolizing enzyme that protects the external granule layer against glucocorticoid receptor stimulation (11B-Hydroxysteroid-Dehydrogenase-Type 2; HSD2) naturally disappears. Here we show that HSD2 inhibition or raising corticosterone to adult physiological levels can both independently increase neural progenitor cell apoptosis in the neonatal mouse. Conversely, glucocorticoid receptor antagonism decreased natural physiological apoptosis in this same progenitor cell population suggesting endogenous glucocorticoid stimulation may regulate apoptosis in the external granule layer. We also found that glucocorticoids HSD2 can effectively metabolize generate less external granule layer apoptosis then glucocorticoids this enzyme is ineffective at breaking down. This finding may explain why glucocorticoids this enzyme can metabolize are clinically effective at treating respiratory dysfunction yet seem to produce no neurodevelopmental deficits. Finally, we demonstrate that both acute and chronic glucocorticoid exposure produces external granule layer apoptosis but without appropriate control groups this effect becomes masked. These results are discussed in terms of their implications for glucocortiocid therapy and neurodevelopment during the perinatal period.
doi:10.1016/j.nbd.2011.04.004
PMCID: PMC3114279  PMID: 21530661
apoptosis; neural progenitor cell; cerebellum; glucocorticoid; dexamethasone; betamethasone; bronchopulmonary dysplasia; chronic lung disease; premature birth; neurodevelopment
25.  Vitamin D status and biomarkers of inflammation in runners 
Background and purpose
The extra-skeletal functions of vitamin D - including its role in inflammatory modulation - are now well recognized but have not yet been investigated in an athletic population. Thus, the purpose of this study was to investigate the relationship between vitamin D status and pro- and anti-inflammatory cytokines (as markers of inflammation and immune system function) in endurance athletes.
Patients and methods
We analyzed fasting blood samples from 19 healthy, endurance-trained male and female runners (following a standardized diet and exercise regimen) for vitamin D status (serum 25-hydroxyvitamin D [25(OH)D)] and specific plasma cytokine concentrations (tumor necrosis factor alpha [TNF-α], interferon-gamma [IFN-γ], interleukin [IL]-4, and IL-10). Serum/plasma concentrations were log-transformed and simple regression analysis was used to determine significant associations between 25(OH)D and cytokine concentrations.
Results
Forty-two percent of participants had insufficient vitamin D status [25(OH)D< 32 ng/mL], whereas 11% were deficient [25(OH)D < 20 ng/mL]. TNF-α and IL-4 were variable, ranging from 2.9 to 36.4 pg/mL and 0 to 252.1 pg/mL, respectively. Concentrations of IFN-γ and IL-10 were minimal, with means of 6.7 ± 7.0 pg/mL and 4.8 ± 5.1 pg/mL, respectively. Regression analysis revealed a significant inverse association between 25(OH)D and TNF-α concentrations (R2 = 56.5, P < 0.001) but not between 25(OH)D and the remaining cytokines, IFN-γ, IL-4, and IL-10 (P = 0.477, 0.694, and 0.673, respectively).
Conclusion
These results call further attention to the epidemic of vitamin D insufficiency, even in outdoor athletes, and support a possible link between decreased vitamin D status and one particular marker of inflammation. Future investigations are necessary to determine whether increased inflammation in athletes with reduced vitamin D status could increase risk for inflammation-related injury.
doi:10.2147/OAJSM.S31022
PMCID: PMC3781897  PMID: 24198585
health; exercise training; tumor necrosis factor alpha; cytokines; injury risk

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