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1.  Setting up a wide panel of patient-derived tumor xenografts of non–small cell lung cancer by improving the preanalytical steps 
Cancer Medicine  2014;4(2):201-211.
With the ongoing need to improve therapy for non–small cell lung cancer (NSCLC) there has been increasing interest in developing reliable preclinical models to test novel therapeutics. Patient-derived tumor xenografts (PDX) are considered to be interesting candidates. However, the establishment of such model systems requires highly specialized research facilities and introduces logistic challenges. We aimed to establish an extensive well-characterized panel of NSCLC xenograft models in the context of a long-distance research network after careful control of the preanalytical steps. One hundred fresh surgically resected NSCLC specimens were shipped in survival medium at room temperature from a hospital-integrated biobank to animal facilities. Within 24 h post-surgery, tumor fragments were subcutaneously xenografted into immunodeficient mice. PDX characterization was performed by histopathological, immunohistochemical, aCGH and next-generation sequencing approaches. For this model system, the tumor take rate was 35%, with higher rates for squamous carcinoma (60%) than for adenocarcinoma (13%). Patients for whom PDX tumors were obtained had a significantly shorter disease-free survival (DFS) compared to patients for whom no PDX tumors (P = 0.039) were obtained. We established a large panel of PDX NSCLC models with a high frequency of mutations (29%) in EGFR, KRAS, NRAS, MEK1, BRAF, PTEN, and PI3KCA genes and with gene amplification (20%) of c-MET and FGFR1. This new patient-derived NSCLC xenograft collection, established regardless of the considerable time required and the distance between the clinic and the animal facilities, recapitulated the histopathology and molecular diversity of NSCLC and provides stable and reliable preclinical models for human lung cancer research.
doi:10.1002/cam4.357
PMCID: PMC4329004  PMID: 25470237
Molecular pathology; NSCLC; PDX; preanalytical
2.  Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA 
Scientific Reports  2015;5:7928.
We evaluated the quality and content of fish oil supplements in New Zealand. All encapsulated fish oil supplements marketed in New Zealand were eligible for inclusion. Fatty acid content was measured by gas chromatography. Peroxide values (PV) and anisidine values (AV) were measured, and total oxidation values (Totox) calculated. Only 3 of 32 fish oil supplements contained quantities of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that were equal or higher than labelled content, with most products tested (69%) containing <67%. The vast majority of supplements exceeded recommended levels of oxidation markers. 83% products exceeded the recommended PV levels, 25% exceeded AV thresholds, and 50% exceeded recommended Totox levels. Only 8% met the international recommendations, not exceeding any of these indices. Almost all fish oil supplements available in the New Zealand market contain concentrations of EPA and DHA considerably lower than claimed by labels. Importantly, the majority of supplements tested exceeded the recommended indices of oxidative markers. Surprisingly, best-before date, cost, country of origin, and exclusivity were all poor markers of supplement quality.
doi:10.1038/srep07928
PMCID: PMC4300506  PMID: 25604397
4.  Current challenges for detection of circulating tumor cells and cell-free circulating nucleic acids, and their characterization in non-small cell lung carcinoma patients. What is the best blood substrate for personalized medicine? 
The practice of “liquid biopsy” as a diagnostic, prognostic and theranostic tool in non-small cell lung cancer (NSCLC) patients is an appealing approach, at least in theory, since it is noninvasive and easily repeated. In particular, this approach allows patient monitoring during treatment, as well as the detection of different genomic alterations that are potentially accessible to targeted therapy or are associated with treatment resistance. However, clinical routine practice is slow to adopt the liquid biopsy. Several reasons may explain this: (I) the vast number of methods described for potential detection of circulating biomarkers, without a consensus on the ideal technical approach; (II) the multiplicity of potential biomarkers for evaluation, in particular, circulating tumor cells (CTCs) vs. circulating tumor DNA (ctDNA); (III) the difficulty in controlling the pre-analytical phase to obtain robust and reproducible results; (IV) the present cost of the currently available techniques, which limits accessibility to patients; (V) the turnaround time required to obtain results that are incompatible with the urgent need for delivery of treatment. The purpose of this review is to describe the main advances in the field of CTC and ctDNA detection in NSCLC patients and to compare the main advantages and disadvantages of these two approaches.
doi:10.3978/j.issn.2305-5839.2014.08.11
PMCID: PMC4245510  PMID: 25489581
Lung cancer; circulating tumor cells (CTCs); circulating tumor DNA (ctDNA); personalized medicine; methods; pre-analytical phase
5.  “Sentinel” Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2014;9(10):e111597.
Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. Migration of circulating tumor cells (CTCs) into the blood stream is an early event that occurs during carcinogenesis. We aimed to examine the presence of CTCs in complement to CT-scan in COPD patients without clinically detectable lung cancer as a first step to identify a new marker for early lung cancer diagnosis. The presence of CTCs was examined by an ISET filtration-enrichment technique, for 245 subjects without cancer, including 168 (68.6%) COPD patients, and 77 subjects without COPD (31.4%), including 42 control smokers and 35 non-smoking healthy individuals. CTCs were identified by cytomorphological analysis and characterized by studying their expression of epithelial and mesenchymal markers. COPD patients were monitored annually by low-dose spiral CT. CTCs were detected in 3% of COPD patients (5 out of 168 patients). The annual surveillance of the CTC-positive COPD patients by CT-scan screening detected lung nodules 1 to 4 years after CTC detection, leading to prompt surgical resection and histopathological diagnosis of early-stage lung cancer. Follow-up of the 5 patients by CT-scan and ISET 12 month after surgery showed no tumor recurrence. CTCs detected in COPD patients had a heterogeneous expression of epithelial and mesenchymal markers, which was similar to the corresponding lung tumor phenotype. No CTCs were detected in control smoking and non-smoking healthy individuals. CTCs can be detected in patients with COPD without clinically detectable lung cancer. Monitoring “sentinel” CTC-positive COPD patients may allow early diagnosis of lung cancer.
doi:10.1371/journal.pone.0111597
PMCID: PMC4216113  PMID: 25360587
6.  Anthropometry, glucose homeostasis, and lipid profile in prepubertal children born early, full, or late term 
Scientific Reports  2014;4:6497.
To examine differences in growth and metabolism in prepubertal children born early term, full term, and late term. We retrospectively studied 294 prepubertal children aged 7.3 years (range 3.0–12.1 years). Children were separated into those born early term (37 0/7–38 6/7 weeks of gestation; n = 68), full term (39 0/7–40 6/7 weeks; n = 179), and late term (41 0/7–41 6/7 weeks; n = 47). Clinical assessments included anthropometry, DXA-derived body composition, fasting lipids, and glucose homeostasis. Statistical models accounted for important confounding factors, such as gender, age, birth weight SDS, birth order, and parental variables. When birth weight was adjusted for sex and gestational age (birth weight SDS), late terms were heavier than both early (p = 0.034) and full (p = 0.020) terms. Early term children were shorter than both full (p = 0.010) and late (p = 0.049) term children, but differences in height disappeared following correction for parents' heights. There were no differences in glucose homeostasis, BMI SDS, adiposity, or fat distribution between groups. Lipid profiles were also similar. When important confounding factors were accounted for, there were no meaningful differences in anthropometry, glucose homeostasis, and lipid profile among children born early term, full term, or late term.
doi:10.1038/srep06497
PMCID: PMC4178288  PMID: 25263327
7.  Evaluating Contextual Processing in Diffusion MRI: Application to Optic Radiation Reconstruction for Epilepsy Surgery 
PLoS ONE  2014;9(7):e101524.
Diffusion MRI and tractography allow for investigation of the architectural configuration of white matter in vivo, offering new avenues for applications like presurgical planning. Despite the promising outlook, there are many pitfalls that complicate its use for (clinical) application. Amongst these are inaccuracies in the geometry of the diffusion profiles on which tractography is based, and poor alignment with neighboring profiles. Recently developed contextual processing techniques, including enhancement and well-posed geometric sharpening, have shown to result in sharper and better aligned diffusion profiles. However, the research that has been conducted up to now is mainly of theoretical nature, and so far these techniques have only been evaluated by visual inspection of the diffusion profiles. In this work, the method is evaluated in a clinically relevant application: the reconstruction of the optic radiation for epilepsy surgery. For this evaluation we have developed a framework in which we incorporate a novel scoring procedure for individual pathways. We demonstrate that, using enhancement and sharpening, the extraction of an anatomically plausible reconstruction of the optic radiation from a large amount of probabilistic pathways is greatly improved in three healthy controls, where currently used methods fail to do so. Furthermore, challenging reconstructions of the optic radiation in three epilepsy surgery candidates with extensive brain lesions demonstrate that it is beneficial to integrate these methods in surgical planning.
doi:10.1371/journal.pone.0101524
PMCID: PMC4117467  PMID: 25077946
8.  Autophagy plays a critical role in the degradation of active RHOA, the control of cell cytokinesis and genomic stability 
Cancer research  2013;73(14):4311-4322.
Degradation of signaling proteins is one of the most powerful tumor suppressive mechanisms by which a cell can control its own growth. Here, we identify RHOA as the molecular target by which autophagy maintains genomic stability. Specifically, inhibition of autophagosome degradation by the loss of the v-ATPase a3 (TCIRG1) subunit is sufficient to induce aneuploidy. Underlying this phenotype, active RHOA is sequestered via p62 (SQSTM1) within autolysosomes, and fails to localize to the plasma membrane or to the spindle midbody. Conversely, inhibition of autophagosome formation by ATG5 shRNA dramatically increases localization of active RHOA at the midbody, followed by diffusion to the flanking zones. As a result, all of the approaches we examined that compromise autophagy (irrespective of the defect: autophagosome formation, sequestration or degradation) drive cytokinesis failure, multinucleation, and aneuploidy, processes that directly have an impact upon cancer progression. Consistently, we report a positive correlation between autophagy defects and the higher expression of RHOA in human lung carcinoma. We therefore propose that autophagy may act in part as a safeguard mechanism that degrades and thereby maintains the appropriate level of active RHOA at the midbody for faithful completion of cytokinesis and genome inheritance.
doi:10.1158/0008-5472.CAN-12-4142
PMCID: PMC3740229  PMID: 23704209
Autophagy; RHOA; tumor suppression; cytokinesis; aneuploidy
9.  Spatial heterogeneity analysis of brain activation in fMRI 
NeuroImage : Clinical  2014;5:266-276.
In many brain diseases it can be qualitatively observed that spatial patterns in blood oxygenation level dependent (BOLD) activation maps appear more (diffusively) distributed than in healthy controls. However, measures that can quantitatively characterize this spatial distributiveness in individual subjects are lacking. In this study, we propose a number of spatial heterogeneity measures to characterize brain activation maps. The proposed methods focus on different aspects of heterogeneity, including the shape (compactness), complexity in the distribution of activated regions (fractal dimension and co-occurrence matrix), and gappiness between activated regions (lacunarity). To this end, functional MRI derived activation maps of a language and a motor task were obtained in language impaired children with (Rolandic) epilepsy and compared to age-matched healthy controls. Group analysis of the activation maps revealed no significant differences between patients and controls for both tasks. However, for the language task the activation maps in patients appeared more heterogeneous than in controls. Lacunarity was the best measure to discriminate activation patterns of patients from controls (sensitivity 74%, specificity 70%) and illustrates the increased irregularity of gaps between activated regions in patients. The combination of heterogeneity measures and a support vector machine approach yielded further increase in sensitivity and specificity to 78% and 80%, respectively. This illustrates that activation distributions in impaired brains can be complex and more heterogeneous than in normal brains and cannot be captured fully by a single quantity. In conclusion, heterogeneity analysis has potential to robustly characterize the increased distributiveness of brain activation in individual patients.
Highlights
•A number of spatial heterogeneity measures of activation maps were explored in children with Rolandic epilepsy and language impairment•Proposed measures capture the complexity, shape and distribution of brain activation patterns•For a language task all proposed measures revealed that patients exhibit more heterogeneous activation patterns than controls, whereas for a motor task no differences appeared•Spatial heterogeneity of activation patterns is a complex feature that cannot be captured by one single measure, but shape and lacunarity represented the best descriptive measures
doi:10.1016/j.nicl.2014.06.013
PMCID: PMC4141984  PMID: 25161893
Functional magnetic resonance imaging; Spatial heterogeneity; Co-occurrence Matrix; Fractal dimensions; Lacunarity; Activation patterns; BOLD activation maps
10.  Antenatal exercise in overweight and obese women and its effects on offspring and maternal health: design and rationale of the IMPROVE (Improving Maternal and Progeny Obesity Via Exercise) randomised controlled trial 
Background
Obesity during pregnancy is associated with adverse outcomes for the offspring and mother. Lifestyle interventions in pregnancy such as antenatal exercise, are proposed to improve both short- and long-term health of mother and child. We hypothesise that regular moderate-intensity exercise during the second half of pregnancy will result in improved maternal and offspring outcomes, including a reduction in birth weight and adiposity in the offspring, which may be protective against obesity in later life.
Methods/Design
The IMPROVE (Improving Maternal and Progeny Risks of Obesity Via Exercise) study is a two-arm parallel randomised controlled clinical trial being conducted in Auckland, New Zealand. Overweight and obese women (BMI ≥25 kg/m2) aged 18–40 years, with a singleton pregnancy of <20 weeks of gestation, from the Auckland region, are eligible for the trial. Exclusion criteria are ongoing smoking or medical contra-indications to antenatal exercise.
Participants are randomised with 1:1 allocation ratio to either intervention or control group, using computer-generated randomisation sequences in variable block sizes, stratified on ethnicity and parity, after completion of baseline assessments. The intervention consists of a 16-week structured home-based moderate-intensity exercise programme utilising stationary cycles and heart rate monitors, commencing at 20 weeks of gestation. The control group do not receive any exercise intervention. Both groups undergo regular fetal ultrasonography and receive standard antenatal care. Due to the nature of the intervention, participants are un-blinded to group assignment during the trial.
The primary outcome is offspring birth weight. Secondary offspring outcomes include fetal and neonatal body composition and anthropometry, neonatal complications and cord blood metabolic markers. Maternal outcomes include weight gain, pregnancy and delivery complications, aerobic fitness, quality of life, metabolic markers and post-partum body composition.
Discussion
The results of this trial will provide valuable insights on the effects of antenatal exercise on health outcomes in overweight and obese mothers and their offspring.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12612000932864.
doi:10.1186/1471-2393-14-148
PMCID: PMC4002538  PMID: 24767604
Pregnancy; Overweight; Obese; Antenatal exercise; Offspring; Birth weight; Neonatal body composition; Fetal growth; Pregnancy outcomes
11.  Functional and Structural Network Impairment in Childhood Frontal Lobe Epilepsy 
PLoS ONE  2014;9(3):e90068.
In childhood frontal lobe epilepsy (FLE), cognitive impairment and educational underachievement are serious, well-known co-morbidities. The broad scale of affected cognitive domains suggests wide-spread network disturbances that not only involves, but also extends beyond the frontal lobe. In this study we have investigated whole brain connectional properties of children with FLE in relation to their cognitive impairment and compared them with healthy controls. Functional connectivity (FC) of the networks was derived from dynamic fluctuations of resting state fMRI and structural connectivity (SC) was obtained from fiber tractograms of diffusion weighted MRI. The whole brain network was characterized with graph theoretical metrics and decomposed into modules. Subsequently, the graph metrics and the connectivity within and between modules were related to cognitive performance. Functional network disturbances in FLE were related to increased clustering, increased path length, and stronger modularity compared to healthy controls, which was accompanied by stronger within- and weaker between-module functional connectivity. Although structural path length and clustering appeared normal in children with FLE, structural modularity increased with stronger cognitive impairment. It is concluded that decreased coupling between large-scale functional network modules is a hallmark for impaired cognition in childhood FLE.
doi:10.1371/journal.pone.0090068
PMCID: PMC3942412  PMID: 24594874
12.  Poorer glycaemic control is associated with increased skin thickness at injection sites in children with type 1 diabetes 
We aimed to assess the association between skin thickness and glycaemic control in children with type 1 diabetes. Forty-five children (51% males) aged 10.5 ± 2.1 years were studied. Thickness of skin layers were determined by ultrasonography, with participants having ultrasound scans of three anatomical regions (abdomen, thigh, and buttocks). Poorer glycaemic control (increasing HbA1c values) was associated with greater thickness of the dermis (p = 0.015), with an estimated thickening of 87 μm with every 1% increase in HbA1c. Our data suggest that dermal changes associated with poorer glycaemic control in adults are also observed in childhood.
doi:10.1186/1687-9856-2014-2
PMCID: PMC3939813  PMID: 24576336
Type 1 diabetes; Dermis; Subcutaneous tissue; Subcutis; HbA1c
13.  Among overweight middle-aged men, first-borns have lower insulin sensitivity than second-borns 
Scientific Reports  2014;4:3906.
We aimed to assess whether birth order affects metabolism and body composition in overweight middle-aged men. We studied 50 men aged 45.6 ± 5.5 years, who were overweight (BMI 27.5 ± 1.7 kg/m2) but otherwise healthy in Auckland, New Zealand. These included 26 first-borns and 24 second-borns. Insulin sensitivity was assessed by the Matsuda method from an oral glucose tolerance test. Other assessments included DXA-derived body composition, lipid profiles, 24-hour ambulatory blood pressure, and carotid intima-media thickness. First-born men were 6.9 kg heavier (p = 0.013) and had greater BMI (29.1 vs 27.5 kg/m2; p = 0.004) than second-borns. Insulin sensitivity in first-born men was 33% lower than in second-borns (4.38 vs 6.51; p = 0.014), despite adjustment for fat mass. There were no significant differences in ambulatory blood pressure, lipid profile or carotid intima-media thickness between first- and second-borns. Thus, first-born adults may be at a greater risk of metabolic and cardiovascular diseases.
doi:10.1038/srep03906
PMCID: PMC3915551  PMID: 24503677
14.  Effects of Age, Gender, BMI, and Anatomical Site on Skin Thickness in Children and Adults with Diabetes 
PLoS ONE  2014;9(1):e86637.
Objective
We aimed to assess the effects of age, sex, body mass index (BMI), and anatomical site on skin thickness in children and adults with diabetes.
Methods
We studied 103 otherwise healthy children and adolescents with type 1 diabetes aged 5–19 years, and 140 adults with type 1 and type 2 diabetes aged 20–85 years. The thicknesses of both the dermis and subcutis were assessed using ultrasound with a linear array transducer, on abdominal and thigh skin.
Results
There was an age-related thickening of both dermis (p<0.0001) and subcutis (p = 0.013) in children and adolescents. Girls displayed a substantial pubertal increase in subcutis of the thigh (+54%; p = 0.048) and abdomen (+68%; p = 0.009). Adults showed an age-related decrease in dermal (p = 0.021) and subcutis (p = 0.009) thicknesses. Pubertal girls had a thicker subcutis than pubertal boys in both thigh (16.7 vs 7.5 mm; p<0.0001) and abdomen (16.7 vs 8.8 mm; p<0.0001). Men had greater thigh dermal thickness than women (1.89 vs 1.65 mm; p = 0.003), while the subcutis was thicker in women in thigh (21.3 vs 17.9 mm; p = 0.012) and abdomen (17.7 vs 9.8 mm; p<0.0001). In boys, men, and women, both dermis and subcutis were thicker on the abdomen compared to thigh; in girls this was only so for dermal thickness. In both children and adults, the skin (dermis and subcutis) became steadily thicker with increasing BMI (p<0.0001).
Conclusions
Skin thickness is affected by age, pubertal status, gender, BMI, and anatomical site. Such differences may be important when considering appropriate sites for dermal/subcutaneous injections and other transdermal delivery systems.
doi:10.1371/journal.pone.0086637
PMCID: PMC3897752  PMID: 24466182
15.  Increasing BMI is associated with a progressive reduction in physical quality of life among overweight middle-aged men 
Scientific Reports  2014;4:3677.
We assessed whether increasing body mass index (BMI) affects health-related quality of life in a group of 38 overweight (BMI 25–30 kg/m2) middle-aged (45.9 ± 5.4 years) men, recruited in Auckland (New Zealand). Health-related quality of life was assessed with SF-36v2 at 0, 12, and 30 weeks. Increasing BMI was associated with a progressive reduction in physical component summary score (p = 0.008), as well as lower general health (p = 0.036), physical functioning (p = 0.024), and bodily pain (p = 0.030) scores. Stratified analyses confirmed these findings: participants who were more overweight (n = 19; BMI 27.5–30 kg/m2) had poorer physical component summary (p = 0.005), physical functioning (p = 0.040), bodily pain (p = 0.044), and general health (p = 0.073) scores than the less overweight (n = 19; BMI 25–27.5 kg/m2). Increasing BMI is associated with a progressive reduction in physical quality of life, even within a relatively narrow BMI range encompassing only overweight middle-aged men.
doi:10.1038/srep03677
PMCID: PMC3891022  PMID: 24419299
16.  Delayed convergence between brain network structure and function in rolandic epilepsy 
Introduction: Rolandic epilepsy (RE) manifests during a critical phase of brain development, and has been associated with language impairments. Concordant abnormalities in structural and functional connectivity (SC and FC) have been described before. As SC and FC are under mutual influence, the current study investigates abnormalities in the SC-FC synergy in RE.
Methods: Twenty-two children with RE (age, mean ± SD: 11.3 ± 2.0 y) and 22 healthy controls (age 10.5 ± 1.6 y) underwent structural, diffusion weighted, and resting-state functional magnetic resonance imaging (MRI) at 3T. The probabilistic anatomical landmarks atlas was used to parcellate the (sub)cortical gray matter. Constrained spherical deconvolution tractography and correlation of time series were used to assess SC and FC, respectively. The SC-FC correlation was assessed as a function of age for the non-zero structural connections over a range of sparsity values (0.01–0.75). A modularity analysis was performed on the mean SC network of the controls to localize potential global effects to subnetworks. SC and FC were also assessed separately using graph analysis.
Results: The SC-FC correlation was significantly reduced in children with RE compared to healthy controls, especially for the youngest participants. This effect was most pronounced in a left and a right centro-temporal network, as well as in a medial parietal network. Graph analysis revealed no prominent abnormalities in SC or FC network organization.
Conclusion: Since SC and FC converge during normal maturation, our finding of reduced SC-FC correlation illustrates impaired synergy between brain structure and function. More specifically, since this effect was most pronounced in the youngest participants, RE may represent a developmental disorder of delayed brain network maturation. The observed effects seem especially attributable to medial parietal connections, which forms an intermediate between bilateral centro-temporal modules of epileptiform activity, and bear relevance for language function.
doi:10.3389/fnhum.2014.00704
PMCID: PMC4158874  PMID: 25249968
rolandic epilepsy; structural connectivity; functional connectivity; structure-function correlation; brain maturation; graph theory
17.  Reduced Structural Connectivity between Sensorimotor and Language Areas in Rolandic Epilepsy 
PLoS ONE  2013;8(12):e83568.
Introduction
Rolandic epilepsy (RE) is a childhood epilepsy with centrotemporal (rolandic) spikes, that is increasingly associated with language impairment. In this study, we tested for a white matter (connectivity) correlate, employing diffusion weighted MRI and language testing.
Methods
Twenty-three children with RE and 23 matched controls (age: 8–14 years) underwent structural (T1-weighted) and diffusion-weighted MRI (b = 1200 s/mm2, 66 gradient directions) at 3T, as well as neuropsychological language testing. Combining tractography and a cortical segmentation derived from the T1-scan, the rolandic tract were reconstructed (pre- and postcentral gyri), and tract fractional anisotropy (FA) values were compared between patients and controls. Aberrant tracts were tested for correlations with language performance.
Results
Several reductions of tract FA were found in patients compared to controls, mostly in the left hemisphere; the most significant effects involved the left inferior frontal (p = 0.005) and supramarginal (p = 0.004) gyrus. In the patient group, lower tract FA values were correlated with lower language performance, among others for the connection between the left postcentral and inferior frontal gyrus (p = 0.043, R = 0.43).
Conclusion
In RE, structural connectivity is reduced for several connections involving the rolandic regions, from which the epileptiform activity originates. Most of these aberrant tracts involve the left (typically language mediating) hemisphere, notably the pars opercularis of the inferior frontal gyrus (Broca’s area) and the supramarginal gyrus (Wernicke’s area). For the former, reduced language performance for lower tract FA was found in the patients. These findings provide a first microstructural white matter correlate for language impairment in RE.
doi:10.1371/journal.pone.0083568
PMCID: PMC3871667  PMID: 24376719
18.  EBV Infection Is Common in Gingival Epithelial Cells of the Periodontium and Worsens during Chronic Periodontitis 
PLoS ONE  2013;8(12):e80336.
An amplifying role for oral epithelial cells (ECs) in Epstein-Barr Virus (EBV) infection has been postulated to explain oral viral shedding. However, while lytic or latent EBV infections of oro/nasopharyngeal ECs are commonly detected under pathological conditions, detection of EBV-infected ECs in healthy conditions is very rare. In this study, a simple non-surgical tissue sampling procedure was used to investigate EBV infection in the periodontal epithelium that surrounds and attaches teeth to the gingiva. Surprisingly, we observed that the gingival ECs of the periodontium (pECs) are commonly infected with EBV and may serve as an important oral reservoir of latently EBV-infected cells. We also found that the basal level of epithelial EBV-infection is significantly increased in chronic periodontitis, a common inflammatory disease that undermines the integrity of tooth-supporting tissues. Moreover, the level of EBV infection was found to correlate with disease severity. In inflamed tissues, EBV-infected pECs appear to be prone to apoptosis and to produce larger amounts of CCL20, a pivotal inflammatory chemokine that controls tissue infiltration by immune cells. Our discovery that the periodontal epithelium is a major site of latent EBV infection sheds a new light on EBV persistence in healthy carriers and on the role of this ubiquitous virus in periodontitis. Moreover, the identification of this easily accessible site of latent infection may encourage new approaches to investigate and monitor other EBV-associated disorders.
doi:10.1371/journal.pone.0080336
PMCID: PMC3868609  PMID: 24367478
19.  Glasgow Coma Scale and Outcomes after Structural Traumatic Head Injury in Early Childhood 
PLoS ONE  2013;8(12):e82245.
Objective
To assess the association of the Glasgow Coma Scale (GCS) with radiological evidence of head injury (the Abbreviated Injury Scale for the head region, AIS-HR) in young children hospitalized with traumatic head injury (THI), and the predictive value of GCS and AIS-HR scores for long-term impairment.
Methods
Our study involved a 10-year retrospective review of a database encompassing all patients admitted to Starship Children’s Hospital (Auckland, New Zealand, 2000–2010) with THI.
Results
We studied 619 children aged <5 years at the time of THI, with long-term outcome data available for 161 subjects. Both GCS and AIS-HR scores were predictive of length of intensive care unit and hospital stay (all p<0.001). GCS was correlated with AIS-HR (ρ=-0.46; p<0.001), although mild GCS scores (13–15) commonly under-estimated the severity of radiological injury: 42% of children with mild GCS scores had serious–critical THI (AIS-HR 3–5). Increasingly severe GCS or AIS-HR scores were both associated with a greater likelihood of long-term impairment (neurological disability, residual problems, and educational support). However, long-term impairment was also relatively common in children with mild GCS scores paired with structural THI more severe than a simple linear skull fracture.
Conclusion
Severe GCS scores will identify most cases of severe radiological injury in early childhood, and are good predictors of poor long-term outcome. However, young children admitted to hospital with structural THI and mild GCS scores have an appreciable risk of long-term disability, and also warrant long-term follow-up.
doi:10.1371/journal.pone.0082245
PMCID: PMC3846816  PMID: 24312648
20.  Increased Adiposity in Adults Born Preterm and Their Children 
PLoS ONE  2013;8(11):e81840.
Background
Preterm birth is associated with abnormalities in growth, body composition, and metabolism during childhood, but adult data are scarce and none exist for their offspring. We therefore aimed to examine body composition and cardiovascular risk factors in adults born preterm and their children.
Methods
A cohort of 52 adults (aged 35.7 years, 54% female, 31 born preterm) and their term-born children (n=61, aged 8.0 years, 54% female, 60% from a preterm parent) were studied. Auxology and body composition (whole-body dual-energy X-ray absorptiometry) were measured, and fasting blood samples taken for metabolic and hormonal assessments.
Results
Adults born preterm had greater abdominal adiposity, displaying more truncal fat (p=0.006) and higher android to gynoid fat ratio (p=0.004). Although women born preterm and at term were of similar weight and BMI, men born preterm (n=8) were on average 20 kg heavier (p=0.010) and of greater BMI (34.2 vs 28.4 kg/m2; p=0.021) than men born at term (n=16). Adults born preterm also displayed a less favourable lipid profile, including lower HDL-C concentrations (p=0.007) and greater total cholesterol to HDL-C ratio (p=0.047). Children of parents born preterm tended to have more body fat than the children of parents born at term (21.3 vs 17.6%; p=0.055). Even after adjustment for mean parental BMI, children of parents born preterm had altered fat distribution, with more truncal fat (p=0.048) and greater android to gynoid fat ratio (p=0.009).
Conclusions
Adults born preterm, particularly men, have markedly increased fat mass and altered fat distribution. A similar increase in abdominal adiposity was observed in the term born offspring of parents born preterm, indicating that adverse outcomes associated with preterm birth may extend to the next generation.
doi:10.1371/journal.pone.0081840
PMCID: PMC3835734  PMID: 24278462
21.  Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group 
BMC Cancer  2013;13:472.
Background
Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas.
Methods
Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations.
Results
All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P<0.001), and the percentage of samples evaluated by a pathologist for tumour cell content increased, from 75.2% to 96.9% (P<0.001).
Conclusion
Despite the use of non-certified methods, the false response rate was low. Nationwide EQA can improve the quality of molecular pathology tests on tumours.
doi:10.1186/1471-2407-13-472
PMCID: PMC3852250  PMID: 24119386

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