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1.  Tunable Visible and Near IR Photoactivation of Light-Responsive Compounds 
doi:10.1002/anie.201308816
PMCID: PMC4036634  PMID: 24285381
Photochemistry; Energy transfer; Drug delivery; Vitamins; Fluorescence
2.  Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis 
Science (New York, N.Y.)  2014;345(6192):98-101.
Protein folding by the endoplasmic reticulum (ER) is physiologically critical, while its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here we find that unmitigated ER stress promotes apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, allowing time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.
doi:10.1126/science.1254312
PMCID: PMC4284148  PMID: 24994655
3.  A retrospective analysis of myocardial preservation techniques during coronary artery bypass graft surgery: are we protecting the heart? 
Background
Retrograde perfusion into coronary sinus during coronary artery bypass graft (CABG) surgery reduces the need for cardioplegic interruptions and ensures the distribution of cardioplegia to stenosed vessel territories, therefore enhancing the delivery of cardioplegia to the subendocardium. Peri-operative myocardial injury (PMI), as measured by the rise of serum level of cardiac biomarkers, has been associated with short and long-term clinical outcomes. We conducted a retrospective analysis to investigate whether the combination of antegrade and retrograde techniques of cardioplegia delivery is associated with a reduced PMI than that observed with the traditional methods of myocardial preservation.
Methods
Fifty-four consecutive patients underwent CABG surgery using either antegrade cold blood cardioplegia (group 1, n = 28) or cross-clamp fibrillation (group 2, n = 16) or antegrade retrograde warm blood cardioplegia (group 3, n = 10). The study primary end-point was PMI, evaluated with total area under the curve (AUC) of high-sensitivity Troponin-T (hsTnT), measured pre-operatively and at 6, 12, 24, 48 and 72 hours post-surgery. Secondary endpoints were acute kidney injury (AKI) and inotrope scores, length of intensive care unit (ICU) and hospital stay, new onset atrial fibrillation (AF) and clinical outcomes at 6 weeks (death, non-fatal myocardial infarction, coronary artery revascularization, stroke).
Results
There was evidence that mean total AUC of hsTnT was different among the three groups (P = 0.050). In particular mean total AUC of hsTnT was significantly lower in group 3 compared to both group 1 (-16.55; 95% CI: -30.08, -3.01; P = 0.018) with slightly weaker evidence of a lower mean hsTnT in group 3 when compared to group 2 (-15.13; 95% CI -29.87, -0.39; P = 0.044). There was no evidence of a difference when comparing group 2 to group 1 (-1.42,; 95% CI: -12.95, 10.12, P = 0.806).
Conclusions
Our retrospective analysis suggests that, compared to traditional methods of myocardial preservation, antegrade retrograde cardioplegia may reduce PMI in patients undergoing first time CABG surgery.
doi:10.1186/s13019-014-0184-7
PMCID: PMC4301898  PMID: 25551585
Coronary artery bypass graft surgery; Peri-operative myocardial injury; Antegrade cardioplegia; Retrograde cardioplegia; Cross-clamp fibrillation
4.  Primary synovial sarcoma of the lung: can haemothorax be the first manifestation? 
Journal of Thoracic Disease  2014;6(12):E249-E251.
Primary pulmonary synovial sarcomas represent a rare clinical entity and account for approximately 0.5% of lung malignancies. We report the case of a 30-year-old male who presented clinically with haemothorax. Imaging revealed a complex collection obscuring a multi-lobulated mass in the right lower lobe of the lung. He underwent a right thoracotomy for evacuation of collection and surgical resection of his pulmonary mass. Histological analysis confirmed a grade 3 monophasic fibrous synovial sarcoma of the lung with infiltration to adjacent pleura, causing his initial haemothorax. Postoperative period was uneventful and patient was referred to the oncology team for further management. Primary pulmonary synovial sarcoma, though rare, should remain an important differential when considering lung malignancies, as complete surgical resection is the mainstay of treatment.
doi:10.3978/j.issn.2072-1439.2014.11.01
PMCID: PMC4283313  PMID: 25590001
Primary pulmonary synovial sarcoma; haemothorax
5.  Assessing the gene regulatory properties of Argonaute-bound small RNAs of diverse genomic origin 
Nucleic Acids Research  2014;43(1):470-481.
High-throughput sequencing reveals an abundance of microRNA-sized fragments derived from larger non-coding RNAs. Roles for these small RNAs in gene silencing are suggested by their co-precipitation with Argonaute, the microRNA effector protein, though the extent to which they suppress gene expression endogenously remains unclear. To address this, we used luciferase reporters to determine the endogenous functionality of small RNAs from a diverse range of sources. We demonstrate small RNAs derived from snoRNAs have the capacity to act in a microRNA-like manner, though we note the vast majority of these are bound to Argonaute at levels below that required for detectable silencing activity. We show Argonaute exhibits a high degree of selectivity for the small RNAs with which it interacts and note that measuring Argonaute-associated levels is a better indicator of function than measuring total expression. Although binding to Argonaute at sufficient levels is necessary for demonstrating microRNA functionality in our reporter assay, this alone is not enough as some small RNAs derived from other non-coding RNAs (tRNAs, rRNAs, Y-RNAs) are associated with Argonaute at very high levels yet do not serve microRNA-like roles.
doi:10.1093/nar/gku1242
PMCID: PMC4288155  PMID: 25452337
6.  Transcriptional Suppression of CYP2A13 Expression by Lipopolysaccharide in Cultured Human Lung Cells and the Lungs of a CYP2A13-Humanized Mouse Model 
Toxicological Sciences  2013;135(2):476-485.
CYP2A13, a human P450 enzyme preferentially expressed in the respiratory tract, is highly efficient in the metabolic activation of tobacco-specific nitrosamines. The aim of this study was to test the hypothesis that inflammation suppresses CYP2A13 expression in the lung, thus explaining the large interindividual differences in CYP2A13 levels previously found in human lung biopsy samples. We first demonstrated that the bacterial endotoxin lipopolysaccharide (LPS) and the proinflammatory cytokine IL-6 can suppress CYP2A13 messenger RNA (mRNA) expression in the NCI-H441 human lung cell line. We then report that an ip injection of LPS (1mg/kg), which induces systemic and lung inflammation, caused substantial reductions in CYP2A13 mRNA (~50%) and protein levels (~80%) in the lungs of a newly generated CYP2A13-humanized mouse model. We further identified two critical CYP2A13 promoter regions, one (major) between −484 and −1008bp and the other (minor) between −134 and −216bp, for the response to LPS, through reporter gene assays in H441 cells. The potential involvement of the nuclear factor NF-κB in LPS-induced CYP2A13 downregulation was suggested by identification of putative NF-κB binding sites within the LPS response regions and effects of an NF-κB inhibitor (pyrrolidine dithiocarbamate) on CYP2A13 expression in H441 cells. Results from gel shift assays further confirmed binding of NF-κB-like nuclear proteins of H441 cells to the major LPS response region of the CYP2A13 promoter. Thus, our findings strongly support the hypothesis that CYP2A13 levels in human lung can be suppressed by inflammation associated with disease status in tissue donors, causing underestimation of CYP2A13 levels in healthy lung.
doi:10.1093/toxsci/kft165
PMCID: PMC3807623  PMID: 23884085
CYP2A; LPS; lung; inflammation; chemical carcinogenesis.
7.  The challenging management of lung choriocarcinoma 
Journal of Thoracic Disease  2014;6(10):E220-E222.
The purpose of this paper is to highlight the existence and the management of lung choriocarcinoma (CCA), a rare category of lung tumors. We present a 42-year-old female that presented to our department with a PET positive lesion in the left upper lobe and a history of pregnancy 6 months prior to onset of symptoms. CT guided biopsy was inconclusive for diagnosis and the patient underwent a left thoracotomy and lingula sparing upper lobectomy. Histology revealed CCA of the lung and subsequently blood results confirmed the elevated b-HCG. CCA of the lung is a clinical entity that should be considered in the differential diagnosis of lung lesions in women after pregnancy.
doi:10.3978/j.issn.2072-1439.2014.09.18
PMCID: PMC4215135  PMID: 25364535
Choriocarcinoma (CCA); lung metastases; pregnancy
8.  Primary mucoepidermoid carcinoma of the thymus presenting with myasthenia gravis 
Journal of Thoracic Disease  2014;6(10):E223-E225.
Mucoepidermoid carcinoma (MEC) of the thymus is a rare malignant neoplasm of the anterior mediastinum. There are less than 30 cases described in the English literature. We report a case of a 47-year-old lady who presented with myasthenia gravis and was found to have a well-circumscribed anterior mediastinal mass in her medical work-up. This mass was surgically resected and subsequently found to be a primary MEC of the thymus. This is the first reported case of thymic MEC with concurrent myasthenia gravis. Her myasthenia symptoms have persisted following complete surgical resection of her tumour.
doi:10.3978/j.issn.2072-1439.2014.09.19
PMCID: PMC4215142  PMID: 25364536
Mucoepidermoid carcinoma (MEC); thymus; myasthenia gravis
9.  A broad spectrum dark quencher: construction of multiple colour protease and photolytic sensors† 
An anthraquinone-based fluorescent quencher is described that is applicable to fluorophores throughout the visible spectrum and into the near IR. This species has been used to construct a palate of multicolour sensors of proteolysis and photolysis.
doi:10.1039/c3cc42628a
PMCID: PMC4167382  PMID: 23778327
10.  Lipid Pools As Photolabile “Protecting Groups”: Design of Light-Activatable Bioagents 
Angewandte Chemie (International ed. in English)  2013;52(38):10.1002/anie.201305510.
Lipidated light-responsive constructs that sequester bioagents to the membranes of organelles and cells have been constructed. When membrane-bound, the bioagent is not susceptible to processing by its biological target. Photolysis releases the bioagent from its membrane anchor and thereby renders it biologically active.
doi:10.1002/anie.201305510
PMCID: PMC3840492  PMID: 23904389
Photolysis; Phosphorylation; Biosensors; Fluorescent probes; Cell adhesion
11.  Structural genomics of protein phosphatases 
The New York SGX Research Center for Structural Genomics (NYSGXRC) of the NIGMS Protein Structure Initiative (PSI) has applied its high-throughput X-ray crystallographic structure determination platform to systematic studies of all human protein phosphatases and protein phosphatases from biomedically-relevant pathogens. To date, the NYSGXRC has determined structures of 21 distinct protein phosphatases: 14 from human, 2 from mouse, 2 from the pathogen Toxoplasma gondii, 1 from Trypanosoma brucei, the parasite responsible for African sleeping sickness, and 2 from the principal mosquito vector of malaria in Africa, Anopheles gambiae. These structures provide insights into both normal and pathophysiologic processes, including transcriptional regulation, regulation of major signaling pathways, neural development, and type 1 diabetes. In conjunction with the contributions of other international structural genomics consortia, these efforts promise to provide an unprecedented database and materials repository for structure-guided experimental and computational discovery of inhibitors for all classes of protein phosphatases.
doi:10.1007/s10969-007-9036-1
PMCID: PMC4163028  PMID: 18058037
Structural genomics; Phosphatase; NYSGXRC; X-ray crystallography
12.  The challenging management of hepatopulmonary fistulas 
Journal of Thoracic Disease  2014;6(9):1336-1339.
Hepatopulmonary fistula although benign in nature carries an unacceptable mortality risk up to 10.3% in some case series mainly due to surgical complications. From the first description by Ferguson and Burford in 1967 till present different approaches have been applied and with the introduction of less invasive techniques the results have significantly improved. Interestingly the prevalence of the different etiological factors has changed over the years especially with the advance of liver ablating techniques and surgery. A step by step approach to this entity, from diagnosis to treatment has to be reestablished in order to identify the role of interventional modalities and to develop a management algorithm.
doi:10.3978/j.issn.2072-1439.2014.07.19
PMCID: PMC4178102  PMID: 25276379
Hepatopulmonary fistulas; hydatic liver disease; hybrid approach
13.  Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study 
PLoS Biology  2014;12(7):e1001906.
TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse.
The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.
doi:10.1371/journal.pbio.1001906
PMCID: PMC4086714  PMID: 25003521
14.  Risk Factors for Low Receptive Vocabulary Abilities in the Preschool and Early School Years in the Longitudinal Study of Australian Children 
PLoS ONE  2014;9(7):e101476.
Receptive vocabulary development is a component of the human language system that emerges in the first year of life and is characterised by onward expansion throughout life. Beginning in infancy, children's receptive vocabulary knowledge builds the foundation for oral language and reading skills. The foundations for success at school are built early, hence the public health policy focus on reducing developmental inequalities before children start formal school. The underlying assumption is that children's development is stable, and therefore predictable, over time. This study investigated this assumption in relation to children's receptive vocabulary ability. We investigated the extent to which low receptive vocabulary ability at 4 years was associated with low receptive vocabulary ability at 8 years, and the predictive utility of a multivariate model that included child, maternal and family risk factors measured at 4 years. The study sample comprised 3,847 children from the first nationally representative Longitudinal Study of Australian Children (LSAC). Multivariate logistic regression was used to investigate risks for low receptive vocabulary ability from 4–8 years and sensitivity-specificity analysis was used to examine the predictive utility of the multivariate model. In the multivariate model, substantial risk factors for receptive vocabulary delay from 4–8 years, in order of descending magnitude, were low receptive vocabulary ability at 4 years, low maternal education, and low school readiness. Moderate risk factors, in order of descending magnitude, were low maternal parenting consistency, socio-economic area disadvantage, low temperamental persistence, and NESB status. The following risk factors were not significant: One or more siblings, low family income, not reading to the child, high maternal work hours, and Aboriginal or Torres Strait Islander ethnicity. The results of the sensitivity-specificity analysis showed that a well-fitted multivariate model featuring risks of substantive magnitude does not do particularly well in predicting low receptive vocabulary ability from 4–8 years.
doi:10.1371/journal.pone.0101476
PMCID: PMC4079336  PMID: 24988308
15.  Probes of the Mitochondrial cAMP-dependent Protein Kinase 
Biochimica et biophysica acta  2013;1834(7):1359-1363.
The development of a fluorescent assay to detect activity of the mitochondrial cAMP-dependent protein kinase (PKA) is described. A peptide-based sensor was utilized to quantify the relative amount of PKA activity present in each compartment of the mitochondria (the outer membrane, the intermembrane space, and the matrix). In the process of validating this assay, we discovered that PKA activity is regulated by the protease calpain. Upon exposure of bovine heart mitochondria to digitonin, Ca2+, and a variety of electron transport chain inhibitors, the regulatory subunits of the PKA holoenzyme (R2C2) are digested, releasing active catalytic subunits. This proteolysis is attenuated by calpain inhibitor I (ALLN).
doi:10.1016/j.bbapap.2013.02.002
PMCID: PMC3665737  PMID: 23410952
signal transduction; sensor; fluorescent peptide; cAMP-dependent protein kinase (PKA); calpain
16.  Is The Effect of Compulsory Community Treatment on Preventable Deaths From Physical Disorders Mediated by Better Access to Specialized Medical Procedures? 
Objectives
Compulsory community treatment has been shown to reduce preventable deaths from physical disorders—these causes being up to 10 times more common than suicide in psychiatric patients. We investigated whether this was mediated by better access to specialized medical procedures.
Method:
All patients on compulsory community treatment for over 11 years were compared with matched control subjects using linked administrative health data from Western Australia (state population of about 2.24 million). Outcomes were access to revascularization and other specialized procedures at 1-, 2-, and 3-year follow-up. Logistic regression was used to adjust for demographics, prior health service use, diagnosis, and length of psychiatric history.
Results:
There were 2757 patients and 2687 control subjects (total n = 5444). Sixty-five per cent were males (n = 3522), and the average age was 36 years (SD 13.2). Most had schizophrenia or other nonaffective psychoses (74%), followed by affective disorders (26%). At 2-year follow-up, 2% (n = 53) of patients and 2.6% (n = 69) of control subjects had undergone a specialized intervention. Compulsory community treatment did not result in greater access to specialized procedures at all 3 time points even after adjusting for potential confounders.
Conclusions:
Greater access to specialized procedures does not explain the reduced mortality from preventable physical illness that had been reported in patients on community treatment orders. There must be other explanations for this finding, such as mental health staff facilitating access to chronic disease management in primary care. This warrants further research.
PMCID: PMC4079220  PMID: 24444325
community treatment order; mortality; psychiatric services
17.  Higher Maternal Protectiveness Is Associated with Higher Odds of Child Overweight and Obesity: A Longitudinal Australian Study 
PLoS ONE  2014;9(6):e100686.
In recent years there has been an increasing interest in overprotective parenting and the potential role it plays in child development. While some have argued that a trend towards increased parental fear and reduced opportunity for independent mobility may be linked to increasing rates of child overweight and obesity, there is limited empirical information available to support this claim. Using data from the Longitudinal Study of Australian Children, this study aimed to examine the longitudinal relationships between maternal protectiveness and child overweight and obesity. A cohort of 4–5 year old children was followed up at 6–7, 8–9 and 10–11 years of age (n  =  2596). Measures included a protective parenting scale administered when children were 6–7 and 8–9 years of age, child body mass index (BMI), family characteristics including household income, neighbourhood disadvantage, child's position amongst siblings, and maternal BMI, education, employment, mental health and age at first birth. International Obesity Taskforce age- and sex-specific BMI cut points were used to determine if children were in the normal, overweight or obese BMI range. There was no association between maternal protectiveness and the odds of children being overweight or obese at age 4–5, 6–7 or 8–9 years. However at age 10–11 years, a 1 standard deviation increase in maternal protectiveness was associated with a 13% increase in the odds of children being overweight or obese. The results provide evidence of a relationship between maternal protectiveness and child overweight and obesity, however further research is required to understand the mechanism(s) that links the two concepts.
doi:10.1371/journal.pone.0100686
PMCID: PMC4067382  PMID: 24955586
18.  Measurement of Protein Tyrosine Phosphatase Activity in Single Cells by Capillary Electrophoresis 
Analytical chemistry  2013;85(12):6136-6142.
A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates, and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 ± 250 nM and 290 ± 54 nM, respectively. Dose-response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn2+ and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 ± 8.2 fmol min−1 mg−1) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 ± 0.3 nmol min−1 mg−1). Zn2+, 1,2-naphthoquinone and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 μM, and 100 nM, respectively. Dephosphorylation of the reporter following loading into living single cells occurred at rates of at least 2 pmol min−1 mg−1. When single cells were exposed to 1,2-naphthoquinone (50 μM), Zn2+ (100 μM), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens.
doi:10.1021/ac401106e
PMCID: PMC3704224  PMID: 23682679
19.  Premature return to play and return to learn after a sport-related concussion 
Canadian Family Physician  2014;60(6):e310-e315.
Abstract
Objective
To determine what proportion of patients experience an exacerbation of their symptoms as a result of premature return to play (RTP) and return to learn (RTL) following sport-related concussions.
Design
Retrospective study of electronic medical records from the office-based practice of one family and sport medicine physician who had systematically provided recommendations for cognitive and physical rest based on existing consensus recommendations. Two blinded authors independently reviewed each chart, which included Sport Concussion Assessment Tool (SCAT) and SCAT2 symptom self-report forms to determine whether an athlete had returned to play or learn prematurely. If there was a discrepancy between the 2 reviewers then a third author reviewed the charts.
Setting
A sport medicine and family practice in Ontario. The physician assessed sport-related concussions after self-referral or referral from other primary care physicians, teams, and schools.
Participants
A total of 170 charts of 159 patients were assessed for sport-related concussion during a 5-year period (April 2006 to March 2011). All participants were students who were participating in sports at the time of injury. There were 41 concussions in elementary students, 95 concussions in high school students, and 34 concussions in college or university students.
Main outcome measures
Premature RTP and RTL were defined as chart records documenting the recurrence or worsening of symptoms that accompanied the patients’ RTP or RTL. Measures were compared using the earliest available SCAT forms and self-reporting.
Results
In 43.5% of concussion cases, the patient returned to sport too soon and in 44.7% of concussion cases, the patient returned to school too soon. Patients with a history of previous concussion required more days of rest before being permitted to participate in any physical activity than those patients without a previous history of concussion. Elementary school students required fewer days of rest before being permitted to return to any physical activity compared with high school students and college or university students.
Conclusion
Currently, physicians recommend restrictions on mental and physical activity following sport-related concussion. This is done without clear guidelines as to what cognitive rest entails for students. Further research is required to determine how to implement a management plan for student athletes to facilitate complete recovery after concussion.
PMCID: PMC4055342  PMID: 24925965
20.  Maternal Exposure to Mercury Chloride During Pregnancy and Lactation Affects the Immunity and Social Behavior of Offspring 
Toxicological Sciences  2013;133(1):101-111.
Developmental HgCl2 exposures of F1 offspring (H-2q/s) from unsociable SJL/J (H-2s) dams with high susceptibility to Hg-induced autoimmunity (SFvF1) and from highly sociable FVB/NJ (FVB; H-2q) dams with lower susceptibility to Hg-induced autoimmunity (FvSF1) were investigated. Hg exposure increased the serum IgG levels of all offspring at postnatal day 21 (pnd21) and of SJL/J dams but not of FVB dams. Serum IgG anti-brain antibody (Ab) levels of pnd21 SFvF1 offspring and SJL dams were higher than those of the FvSF1 offspring and FVB dams, but Hg only increased the titers of the FVB dams and their offspring. Hg significantly elevated the presence of IgG in all brain regions of the pnd21 SFvF1 offspring, and the SFvF1 offspring had greater amounts of IgG in the brain than the FvSF1 offspring, which had Hg-induced increases in only two brain regions. Cytokine levels were elevated in the brain regions of Hg-treated pnd21 SFvF1 but not of FvSF1 offspring, and SFvF1 females had more brain regions expressing cytokines than the males. At pnd70, the serum IgG, serum antibrain Abs, amounts of brain IgG, and brain cytokine levels of all of the Hg-treated offspring were equivalent to those of their appropriate controls, suggesting that developmental Hg exposure did not induce chronic immunological effects. However, the social behaviors of Hg-exposed SFvF1 offspring at pnd70 were significantly impaired, and SFvF1 females displayed greater decline in social behaviors than males, suggesting that the higher neuroinflammation of SFvF1 females earlier in life is associated with the altered behavior. Thus, developmental Hg exposure induces long-lasting effects on social behavior of offspring, which is dependent on sex and genetics and the induction of neuroinflammation.
doi:10.1093/toxsci/kft023
PMCID: PMC3693512  PMID: 23392568
mercury; mouse social behavior; IgG antibrain antibodies; maternal influences.
21.  Gaps in Indigenous disadvantage not closing: a census cohort study of social determinants of health in Australia, Canada, and New Zealand from 1981–2006 
BMC Public Health  2014;14:201.
Background
Australia, Canada, and New Zealand are all developed nations that are home to Indigenous populations which have historically faced poorer outcomes than their non-Indigenous counterparts on a range of health, social, and economic measures. The past several decades have seen major efforts made to close gaps in health and social determinants of health for Indigenous persons. We ask whether relative progress toward these goals has been achieved.
Methods
We used census data for each country to compare outcomes for the cohort aged 25–29 years at each census year 1981–2006 in the domains of education, employment, and income.
Results
The percentage-point gaps between Indigenous and non-Indigenous persons holding a bachelor degree or higher qualification ranged from 6.6% (New Zealand) to 10.9% (Canada) in 1981, and grew wider over the period to range from 19.5% (New Zealand) to 25.2% (Australia) in 2006. The unemployment rate gap ranged from 5.4% (Canada) to 16.9% (Australia) in 1981, and fluctuated over the period to range from 6.6% (Canada) to 11.0% (Australia) in 2006. Median Indigenous income as a proportion of non-Indigenous median income (whereby parity = 100%) ranged from 77.2% (New Zealand) to 45.2% (Australia) in 1981, and improved slightly over the period to range from 80.9% (Canada) to 54.4% (Australia) in 2006.
Conclusions
Australia, Canada, and New Zealand represent nations with some of the highest levels of human development in the world. Relative to their non-Indigenous populations, their Indigenous populations were almost as disadvantaged in 2006 as they were in 1981 in the employment and income domains, and more disadvantaged in the education domain. New approaches for closing gaps in social determinants of health are required if progress on achieving equity is to improve.
doi:10.1186/1471-2458-14-201
PMCID: PMC3937433  PMID: 24568143
Indigenous; Inequality; Social determinants of health; Education; Unemployment; Income
22.  “Deeply Quenched” Monitoring of Protein Arginine Deiminase Activity: Multicolor Visualization of Citrullination** 
doi:10.1002/anie.201208464
PMCID: PMC3752692  PMID: 23339123
protein arginine deiminase; citrullination; fluorescent sensor; multicolor visualization; epigenetics
23.  Top-Cited Articles in Traumatic Brain Injury 
A review of the top-cited articles in a scientific discipline can identify areas of research that are well established and those in need of further development, and may, as a result, inform and direct future research efforts. Our objective was to identify and characterize the top-cited articles in traumatic brain injury (TBI). We used publically available software to identify the 50 TBI articles with the most lifetime citations, and the 50 TBI articles with the highest annual citation rates. A total of 73 articles were included in this review, with 27 of the 50 papers with the highest annual citation rates common to the cohort of 50 articles with the most lifetime citations. All papers were categorized by their primary topic or focus, namely: predictor of outcome, pathology/natural history, treatment, guidelines and consensus statements, epidemiology, assessment measures, or experimental model of TBI. The mean year of publication of the articles with the most lifetime citations and highest annual citation rates was 1990 ± 14.9 years and 2003 ± 6.7 years, respectively. The 50 articles with the most lifetime citations typically studied predictors of outcome (34.0%, 17/50) and were specific to severe TBI (38.0%, 19/50). In contrast, the most common subject of papers with the highest annual citation rates was treatment of brain injury (22.0%, 11/50), and these papers most frequently investigated mild TBI (36.0%, 18/50). These findings suggest an intensified focus on mild TBI, which is perhaps a response to the dedicated attention these injuries are currently receiving in the context of sports and war, and because of their increasing incidence in developing nations. Our findings also indicate increased focus on treatment of TBI, possibly due to the limited efficacy of current interventions for brain injury. This review provides a cross-sectional summary of some of the most influential articles in TBI, and a bibliometric examination of the current status of TBI research.
doi:10.3389/fnhum.2014.00879
PMCID: PMC4220681  PMID: 25414657
traumatic brain injury; head injury; concussion; bibliometric; citation
25.  A three generation study of the mental health relationships between grandparents, parents and children 
BMC Psychiatry  2013;13:299.
Background
It is well known that children of parents with mental illness are at greater risk of mental illness themselves. However the patterns of familial mental health problems across multiple generations in families are less clear. This study aimed to examine mental health relationships across three generations of Australian families.
Methods
Mental health data, along with a range of family demographic information, were collected from over 4600 families in Growing Up in Australia: The Longitudinal Study of Australian Children, a nationally representative cohort study. The social and emotional wellbeing of two cohorts of children aged 4–5 years and 8–9 years was measured using the parent-rated Strengths and Difficulties Questionnaire (SDQ). The mental health of mothers and fathers was measured using the Kessler 6-item K6 scale, and the mental health history of maternal and paternal grandmothers and grandfathers was measured using a dichotomous parent-report item. Multivariate linear regression analyses were used assess the relationships between grandparent and parent mental health and child social and emotional wellbeing at ages 4–5 years and 8–9 years.
Results
Both cohorts of children had greater mental health distress with higher SDQ scores on average if their mother or father had a mental health problem. For children aged 8–9 years, a history of mental health problems in maternal grandmothers and grandfathers was associated with higher SDQ scores in grandchildren, after controlling for maternal and paternal mental health and other family characteristics. For children aged 4–5 years, only a mental health history in paternal grandfathers was associated with higher SDQ scores.
Conclusions
The mental health histories of both parents and grandparents play an important role in the social and emotional wellbeing of young children.
doi:10.1186/1471-244X-13-299
PMCID: PMC3829660  PMID: 24206921
Intergenerational transfer; Mental health; Children and families

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