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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
16.  Diastolic Function Is Reduced in Adolescents With Type 1 Diabetes in Response to Exercise 
Diabetes Care  2012;35(10):2089-2094.
OBJECTIVE
To determine whether adolescents with type 1 diabetes have left ventricular functional changes at rest and during acute exercise and whether these changes are affected by metabolic control and diabetes duration.
RESEARCH DESIGN AND METHODS
The study evaluated 53 adolescents with type 1 diabetes and 22 control adolescents. Baseline data included peak exercise capacity and body composition by dual-energy X-ray absorptiometry. Left ventricular functional parameters were obtained at rest and during acute exercise using magnetic resonance imaging.
RESULTS
Compared with nondiabetic control subjects, adolescents with type 1 diabetes had lower exercise capacity (44.7 ± 09 vs. 48.5 ± 1.4 mL/kg fat-free mass [FFM]/min; P < 0.05). Stroke volume was reduced in the diabetes group at rest (1.86 ± 0.04 vs. 2.05 ± 0.07 mL/kg FFM; P = 0.02) and during acute exercise (1.89 ± 0.04 vs. 2.17 ± 0.06 mL/kg FFM; P = 0.01). Diabetic adolescents also had reduced end-diastolic volume at rest (2.94 ± 0.06 vs. 3.26 ± 0.09 mL/kg FFM; P = 0.01) and during acute exercise (2.78 ± 0.05 vs. 3.09 ± 0.08 mL/kg FFM; P = 0.01). End-systolic volume was lower in the diabetic group at rest (1.08 ± 0.03 vs. 1.21 ± 0.04 mL/kg FFM; P = 0.01) but not during acute exercise. Exercise capacity and resting and exercise stroke volumes were correlated with glycemic control but not with diabetes duration.
CONCLUSIONS
Adolescents with type 1 diabetes have reduced exercise capacity and display alterations in cardiac function compared with nondiabetic control subjects, associated with reduced stroke volume during exercise.
doi:10.2337/dc11-2331
PMCID: PMC3447841  PMID: 22773700
17.  Insulin Sensitivity and β-Cell Function in Adults Born Preterm and Their Children 
Diabetes  2012;61(10):2479-2483.
We aimed to evaluate insulin secretion and insulin sensitivity in adults born preterm and their children. Subjects were adults born both preterm and at term, with their children aged 5–10 years born at term. Insulin sensitivity and secretion were assessed using hyperglycemic clamps in adults and frequently sampled intravenous glucose tolerance tests using Bergman minimal model in children. In total, 52 adults aged 34–38 years participated (31 born preterm, mean gestational age 33.3 weeks). Adults born preterm were less insulin sensitive than those born at term (19.0 ± 2.5 vs. 36.3 ± 5.2 mg ⋅ kg−1 ⋅ min−1mU ⋅ L; P < 0.05) with compensatory increased first-phase insulin secretion (56.1 ± 8.5 vs. 25.3 ± 3.7 mU/L; P < 0.001) but similar disposition index indicating appropriate insulin secretion. These differences were independent of sex and remained when subjects born <32 weeks' gestation were excluded from analyses. In total, 61 children were studied (37 of preterm parents, mean age 7.9 ± 0.3 years). Children of parents born preterm had similar insulin sensitivity to children of parents born at term, but a correlation between parental and offspring insulin sensitivity was noted only among children of parents born preterm. In conclusion, adults born preterm have insulin resistance in midadulthood, but this was not associated with insulin resistance in their children.
doi:10.2337/db11-1672
PMCID: PMC3447901  PMID: 22596051
18.  Cost-effectiveness of CTA, MRA and DSA in patients with non-traumatic subarachnoid haemorrhage 
Insights into Imaging  2013;4(4):499-507.
Objectives
Intra-arterial digital subtraction angiography (DSA), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) are imaging modalities used for diagnostic work-up of non-traumatic subarachnoid haemorrhage. The aim of our study was to compare the cost-effectiveness of MRA, DSA and CTA in the first year after the bleed.
Methods
A decision model was used to calculate costs and benefits (in quality-adjusted life-years [QALYs]) that accrued to cohorts of 1,000 patients. Costs and characteristics of diagnostic tests, therapy, patients’ quality of life and associated costs were respected. The diagnostic strategy with highest QALYs and lowest costs was considered most cost-effective.
Results
DSA was the most effective diagnostic option, yielding on average 0.6039 QALYs (95 % CI, 0.5761–0.6327) per patient, followed by CTA 0.5983 QALYs (95 % CI, 0.5704–0.6278) and MRA 0.5947 QALYs (95 % CI, 0.5674–0.6237). Cost was lowest for DSA (39,808 €; 95 % CI, 37,182–42,663), followed by CTA (40,748 €; 95 % CI, 37,937–43,831) and MRA (41,814 €; 95 % CI, 38,730–45,146). A strategy of CTA followed by DSA if CTA was negative or coiling deemed not feasible, was as effective as DSA alone at average costs of 39,767€ (95 % CI, 36,903–42,402).
Conclusion
A combined strategy of CTA and DSA was found to be the most cost-effective diagnostic approach.
Main Messages
• We defined a standard model for cost-effectiveness analysis in diagnostic imaging.
• Comparing total 1-year health costs and benefits, CTA is superior to MRA.
• A strategy of combining CTA and DSA was found to be the most cost-effective diagnostic approach.
doi:10.1007/s13244-013-0264-6
PMCID: PMC3731460  PMID: 23839858
Intracranial aneurysm; Cost effectiveness; Digital subtraction angiography; Magnetic resonance angiography; Computed tomography angiography
19.  Pre-Pubertal Children Born Post-Term Have Reduced Insulin Sensitivity and Other Markers of the Metabolic Syndrome 
PLoS ONE  2013;8(7):e67966.
Background
There are no data on the metabolic consequences of post-term birth (≥42 weeks gestation). We hypothesized that post-term birth would adversely affect insulin sensitivity, as well as other metabolic parameters and body composition in childhood.
Methods
77 healthy pre-pubertal children, born appropriate-for-gestational-age were studied in Auckland, New Zealand: 36 born post-term (18 boys) and 41 (27 boys) born at term (38–40 weeks gestation). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman’s minimal model. Other assessments included fasting hormone concentrations and lipid profiles, body composition from whole-body dual-energy X-ray absorptiometry, 24-hour ambulatory blood pressure monitoring, and inflammatory markers.
Results
Insulin sensitivity was 34% lower in post-term than in term children (7.7 vs. 11.6 x10-4·min-1·(mU/l); p<0.0001). There was a compensatory increase in acute insulin response among post-term children (418 vs 304 mU/l; p=0.037), who also displayed lower glucose effectiveness than those born at term (2.25 vs 3.11 x10-2·min-1; p=0.047). Post-term children not only had more body fat (p=0.014) and less fat-free mass (p=0.014), but also had increased central adiposity with more truncal fat (p=0.017) and greater android to gynoid fat ratio (p=0.007) compared to term controls. Further, post-term children displayed other markers of the metabolic syndrome: lower normal nocturnal systolic blood pressure dipping (p=0.027), lower adiponectin concentrations (p=0.005), as well as higher leptin (p=0.008) and uric acid (p=0.033) concentrations. Post-term boys (but not girls) also displayed a less favourable lipid profile, with higher total cholesterol (p=0.018) and LDL-C (p=0.006) concentrations, and total cholesterol to HDL-C ratio (p=0.048).
Conclusions
Post-term children have reduced insulin sensitivity and display a number of early markers of the metabolic syndrome. These findings could have important implications for the management of prolonged pregnancies. Future studies need to examine potential impacts later in life, as well as possible underlying mechanisms.
doi:10.1371/journal.pone.0067966
PMCID: PMC3698136  PMID: 23840881
20.  Quantifying the use of bioresources for promoting their sharing in scientific research 
GigaScience  2013;2:7.
An increasing portion of biomedical research relies on the use of biobanks and databases. Sharing of such resources is essential for optimizing knowledge production. A major obstacle for sharing bioresources is the lack of recognition for the efforts involved in establishing, maintaining and sharing them, due to, in particular, the absence of adequate tools. Increasing demands on biobanks and databases to improve access should be complemented with efforts of end-users to recognize and acknowledge these resources. An appropriate set of tools must be developed and implemented to measure this impact.
To address this issue we propose to measure the use in research of such bioresources as a value of their impact, leading to create an indicator: Bioresource Research Impact Factor (BRIF). Key elements to be assessed are: defining obstacles to sharing samples and data, choosing adequate identifier for bioresources, identifying and weighing parameters to be considered in the metrics, analyzing the role of journal guidelines and policies for resource citing and referencing, assessing policies for resource access and sharing and their influence on bioresource use. This work allows us to propose a framework and foundations for the operational development of BRIF that still requires input from stakeholders within the biomedical community.
doi:10.1186/2047-217X-2-7
PMCID: PMC3655103  PMID: 23634721
Data sharing; Bioresource; Biobank; Identifier; Metrics; Traceability; Impact factor; Biology; Science policy; Open data
21.  Oxidation of Marine Omega-3 Supplements and Human Health 
BioMed Research International  2013;2013:464921.
Marine omega-3 rich oils are used by more than a third of American adults for a wide range of purported benefits including prevention of cardiovascular disease. These oils are highly prone to oxidation to lipid peroxides and other secondary oxidation products. Oxidized oils may have altered biological activity making them ineffective or harmful, though there is also evidence that some beneficial effects of marine oils could be mediated through lipid peroxides. To date, human clinical trials have not reported the oxidative status of the trial oil. This makes it impossible to understand the importance of oxidation to efficacy or harm. However, animal studies show that oxidized lipid products can cause harm. Oxidation of trial oils may be responsible for the conflicting omega-3 trial literature, including the prevention of cardiovascular disease. The oxidative state of an oil can be simply determined by the peroxide value and anisidine value assays. We recommend that all clinical trials investigating omega-3 harms or benefits report the results of these assays; this will enable better understanding of the benefits and harms of omega-3 and the clinical importance of oxidized supplements.
doi:10.1155/2013/464921
PMCID: PMC3657456  PMID: 23738326
22.  Structural Brain Changes in Migraine 
Context
A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)–measured ischemic lesions in the brain.
Objective
To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline.
Design, Setting, and Participants
In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective populationbased observational study of Dutch participants with migraine and an age- and sexmatched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43–72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44–71 years), and 69% were women.
Main Outcome Measures
Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured.
Results
Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0–4.1; P=.04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in themigraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0–59.5; P=.05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P=.07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores ( 3.7 in the migraine group vs 1.4 in the control group; 95% CI, 4.4 to 0.2; adjusted P=.07).
Conclusions
In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.
doi:10.1001/jama.2012.14276
PMCID: PMC3633206  PMID: 23150008
23.  Early onset of cortical thinning in children with rolandic epilepsy☆ 
NeuroImage : Clinical  2013;2:434-439.
Introduction
Rolandic epilepsy, a childhood epilepsy associated with language impairments, was investigated for language-related cortical abnormalities.
Methods
Twenty-four children with rolandic epilepsy and 24 controls (age 8–14 years) were recruited and underwent the Clinical Evaluation of Language Fundamentals test. Structural MRI was performed at 3 T (voxel size 1 × 1 × 1 mm3) for fully automated quantitative assessment of cortical thickness. Regression analysis was used to test for differences between patients and controls and to assess the effect of age and language indices on cortical thickness.
Results
For patients the core language score (mean ± SD: 92 ± 18) was lower than for controls (106 ± 11, p = 0.0026) and below the norm of 100 ± 15 (p = 0.047). Patients showed specific impairments in receptive language index (87 ± 19, p = 0.002) and language content index (87 ± 18, p = 0.0016). Cortical thickness was reduced in patients (p < 0.05, multiple-comparisons corrected) in left perisylvian regions. Furthermore, extensive cortical thinning with age was found in predominantly left-lateralized frontal, centro-parietal and temporal regions. No associations were found between cortical thickness and language indices in the regions of aberrant cortex.
Conclusion
The cortical abnormalities described represent subtle but significant pathomorphology in this critical phase of brain development (8–14 years) and suggest that rolandic epilepsy should not be considered merely a benign condition. Future studies employing longitudinal designs are prompted for further investigations into cerebral abnormalities in RE and associations with cognitive impairment and development.
Highlights
•Children with RE exhibit aberrant cortex in left perisylvian language regions.•Cortical abnormalities comprise reduced cortical thickness.•Extensive regions of earlier onset of cortical thinning were also observed.•Cortical development may provide an important new subject of research in RE.
doi:10.1016/j.nicl.2013.03.008
PMCID: PMC3777705  PMID: 24179797
Cortical thickness (quantitative); Benign rolandic epilepsy of childhood with centro-temporal spikes; Developmental trajectory; Language impairment
24.  Increasing Maternal Age Is Associated with Taller Stature and Reduced Abdominal Fat in Their Children 
PLoS ONE  2013;8(3):e58869.
Background
Maternal age at childbirth continues to increase worldwide. We aimed to assess whether increasing maternal age is associated with changes in childhood height, body composition, and metabolism.
Methods
277 healthy pre-pubertal children, born 37–41 weeks gestation were studied. Assessments included: height and weight corrected for parental measurements, DEXA-derived body composition, fasting lipids, glucose, insulin, and hormonal profiles. Subjects were separated according to maternal age at childbirth: <30, 30–35, and >35 years.
Results
Our cohort consisted of 126 girls and 151 boys, aged 7.4±2.2 years (range 3–10); maternal age at childbirth was 33.3±4.7 years (range 19–44). Children of mothers aged >35 and 30–35 years at childbirth were taller than children of mothers aged <30 years by 0.26 (p = 0.002) and 0.23 (p = 0.042) SDS, respectively. There was a reduction in childhood BMISDS with increasing maternal age at childbirth, and children of mothers aged >35 years at childbirth were 0.61 SDS slimmer than those of mothers <30 years (p = 0.049). Children of mothers aged 30–35 (p = 0.022) and >35 (p = 0.036) years at childbirth had abdominal adiposity reduced by 10% and 13%, respectively, compared to those in the <30 group. Children of mothers aged 30–35 years at childbirth displayed a 19% increase in IGF-I concentrations compared to offspring in <30 group (p = 0.042). Conversely, IGF-II concentrations were lower among the children born to mothers aged 30–35 (6.5%; p = 0.004) and >35 (8.1%; p = 0.005) compared to those of mothers aged <30 years. Girls of mothers aged 30–35 years at childbirth also displayed improved HOMA-IR insulin sensitivity (p = 0.010) compared to girls born to mothers aged <30 years.
Conclusions
Increasing maternal age at childbirth is associated with a more favourable phenotype (taller stature and reduced abdominal fat) in their children, as well as improved insulin sensitivity in girls.
doi:10.1371/journal.pone.0058869
PMCID: PMC3604016  PMID: 23527040
25.  Olive (Olea europaea L.) Leaf Polyphenols Improve Insulin Sensitivity in Middle-Aged Overweight Men: A Randomized, Placebo-Controlled, Crossover Trial 
PLoS ONE  2013;8(3):e57622.
Background
Olive plant leaves (Olea europaea L.) have been used for centuries in folk medicine to treat diabetes, but there are very limited data examining the effects of olive polyphenols on glucose homeostasis in humans.
Objective
To assess the effects of supplementation with olive leaf polyphenols (51.1 mg oleuropein, 9.7 mg hydroxytyrosol per day) on insulin action and cardiovascular risk factors in middle-aged overweight men.
Design
Randomized, double-blinded, placebo-controlled, crossover trial in New Zealand. 46 participants (aged 46.4±5.5 years and BMI 28.0±2.0 kg/m2) were randomized to receive capsules with olive leaf extract (OLE) or placebo for 12 weeks, crossing over to other treatment after a 6-week washout. Primary outcome was insulin sensitivity (Matsuda method). Secondary outcomes included glucose and insulin profiles, cytokines, lipid profile, body composition, 24-hour ambulatory blood pressure, and carotid intima-media thickness.
Results
Treatment evaluations were based on the intention-to-treat principle. All participants took >96% of prescribed capsules. OLE supplementation was associated with a 15% improvement in insulin sensitivity (p = 0.024) compared to placebo. There was also a 28% improvement in pancreatic β-cell responsiveness (p = 0.013). OLE supplementation also led to increased fasting interleukin-6 (p = 0.014), IGFBP-1 (p = 0.024), and IGFBP-2 (p = 0.015) concentrations. There were however, no effects on interleukin-8, TNF-α, ultra-sensitive CRP, lipid profile, ambulatory blood pressure, body composition, carotid intima-media thickness, or liver function.
Conclusions
Supplementation with olive leaf polyphenols for 12 weeks significantly improved insulin sensitivity and pancreatic β-cell secretory capacity in overweight middle-aged men at risk of developing the metabolic syndrome.
Trial Registration
Australian New Zealand Clinical Trials Registry #336317.
doi:10.1371/journal.pone.0057622
PMCID: PMC3596374  PMID: 23516412

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