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Background The World Health Organization recommends artemisinin-based combination (ACT) for the treatment of uncomplicated malaria. Post-licensure safety data on newly registered ACT is critical for evaluating their risk/benefit profile in malaria endemic countries. The clinical safety of the newly registered combination, Eurartesim®, following its introduction into the public health system in four African countries was assessed. Methods This was a prospective, observational, open-label, non-comparative, longitudinal, multi-centre study using cohort event monitoring. Patients with confirmed malaria had their first dose observed and instructed on how to take the second and the third doses at home. Patients were contacted on day 5 ± 2 to assess adherence and adverse events (AEs). Spontaneous reporting of AEs was continued till day 28. A nested cohort who completed full treatment course had repeated electrocardiogram (ECG) measurements to assess effect on QTc interval. Results A total of 10,925 uncomplicated malaria patients were treated with Eurartesim®. Most patients,95% (10,359/10,925), did not report any adverse event following at least one dose of Eurartesim®. A total of 797 adverse events were reported. The most frequently reported, by system organ classification, were infections and infestations (3. 24%) and gastrointestinal disorders (1. 37%). In the nested cohort, no patient had QTcF > 500 ms prior to day 3 pre-dose 3. Three patients had QTcF > 500 ms (509 ms, 501 ms, 538 ms) three to four hours after intake of the last dose. All the QTcF values in the three patients had returned to

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence.CYP17A1is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12–18 years) who were recruited from a genetic founder population. Our results showed that the variant ofCYP17A1rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P=8.3×10-6). Resting BP was not associated with theCYP17A1variant in either sex. These results suggest that, in adolescent males but not females,CYP17A1enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.

BACKGROUND: Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene-environment interaction. METHODS: We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip. RESULTS: We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (-1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the "protective" (fat intake-lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (-3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031). LIMITATIONS: A limitation of our study was its cross-sectional design. CONCLUSION: Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene.

We used a perturb-and-measure approach, by combining transcranial magnetic stimulation (TMS) and positron emission tomography (PET), to examine changes in the primary motor area (M1) and its effective connectivity in stroke patients with chronic motor deficits (>1-year post-stroke) who underwent 3 weeks of constraint-induced movement therapy. During the 3-week period, 7 patients spent 4 h per day performing shaping exercises with the affected arm under our supervision for 14 days and wore a mitt on the unaffected arm at home in situations where safety was not compromised. Anatomical magnetic resonance imaging confirmed that all patients had lesions that encompassed the white matter; no patient had damage in the hand representation of M1. Improvements on various motor tests were observed immediately after therapy and 1 month afterwards. During the TMS/PET sessions, we applied trains of subthreshold 10-Hz repetitive TMS over the hand representation of the ipsilesional and contralesional M1s and varied the number of TMS trains delivered during each scan. The results demonstrate changes in the local response of TMS in the ipsilesional and contralesional M1, changes in the strength of interhemispheric connectivity between M1s, and changes in the effective connectivity of the ipsilesional and contralesional M1s with the non-primary motor areas, the basal ganglia, and the motor nuclei of the thalamus.

When lifting small objects, people apply forces that match the expected weight of the object. This expectation relies in part on information acquired during a previous lift and on associating a certain weight with a particular object. Our study examined the role of the primary motor and dorsal premotor cortices in predicting weight based either on information acquired during a previous lift (no-cue experiment) or on arbitrary color cues associated with a particular weight (cue experiment). In the two experiments, subjects used precision grip to lift two different weights in a series of trials both before and after we applied low-frequency repetitive transcranial magnetic stimulation over the primary motor and dorsal premotor cortices. In the no-cue experiment, subjects did not receive any previous information about which of two weights they would have to lift. In the cue experiment, a color cue provided information about which of the two weights subjects would have to lift. Our results demonstrate a double dissociation in the effects induced by repetitive stimulation. When applied over the primary motor cortex, repetitive stimulation disrupted the scaling of forces based on information acquired during a previous lift. In contrast, when applied over the dorsal premotor cortex, repetitive stimulation disrupted the scaling of forces based on arbitrary color cues. We conclude that the primary motor and dorsal premotor cortices have unique roles during the anticipatory scaling of forces associated with the lifting of different weights.

Our study uses the combined transcranial magnetic stimulation/positron emission tomography (TMS/PET) method for elucidating neural connectivity of the human motor system. We first altered motor excitability by applying low-frequency repetitive TMS over two cortical motor regions in separate experiments: the dorsal premotor and primary motor cortices. We then assessed the consequences of modulating motor excitability by applying single-pulse TMS over the primary motor cortex and measuring: 1) muscle responses with electromyography and 2) cerebral blood flow with PET. Low-frequency repetitive stimulation reduced muscle responses to a similar degree in both experiments. To map networks of brain regions in which activity changes reflected modulation of motor excitability, we generated t-statistical maps of correlations between reductions in muscle response and differences in cerebral blood flow. Low-frequency repetitive stimulation altered neural activity differently in both experiments. Neural modulation occurred in multiple brain regions after dorsal premotor cortex stimulation; these included motor regions in the frontal cortex as well as more associational regions in the parietal and prefrontal cortices. In contrast, neural modulation occurred in a smaller number of brain regions after primary motor cortex stimulation, many of these confined to the motor system. These findings are consistent with the known differences between the dorsal premotor and primary motor cortices in the extent of cortico-cortical anatomical connectivity in the monkey.

Distinct differences in the human voice emerge during adolescence, with males producing deeper and more resonant voices than females by the end of sexual maturation. Using magnetic resonance images of heads and voice recordings obtained in 532 typically developing adolescents, we investigate what might be the drivers of this change in voice, and the subjective judgment of the voice "maleness" and "femaleness". We show clear sex differences in the morphology of voice-related structures during adolescence, with males displaying strong associations between age (and puberty) and both vocal-fold and vocal-tract length; this was not the case in female adolescents. At the same time, males (compared with females) display stronger associations between age (and puberty) with both fundamental frequency and formant position. In males, vocal morphology was a mediator in the relationship between bioavailable testosterone and acoustic indices. Subjective judgment of the voice sex could be predicted by the morphological and acoustic parameters in males only: the length of vocal folds and its acoustic counterpart, fundamental frequency, is a larger predictor of subjective "maleness" of a voice than vocal-tract length and formant position.

Obesity, a major risk factor for cardiometabolic disease, is associated with variations in a number of structural properties in the adult brain, as assessed with magnetic resonance imaging (MRI). In this study, we investigated the cross-sectional relationship between visceral fat (VF), total body fat (TBF) and three MRI parameters in the brains of typically developing adolescents: (i) T1-weighted (T1W) signal intensity; (ii) T1W signal contrast between white matter (WM) and gray matter (GM); and (iii) magnetization transfer ratio (MTR). In a community-based sample of 970 adolescents (12–18 years old, 466 males), VF was quantified using MRI, and total body fat was measured using a multifrequency bioimpedance. T1W images of the brain were used to determine signal intensity in lobar GM and WM, as well as WM:GM signal contrast. A magnetization transfer (MT) sequence of MTON and MTOFF was used to obtain MTR in GM and WM. We found that both larger volumes of VF and more TBF were independently associated with higher signal intensity in WM and higher WM:GM signal contrast, as well as higher MTR in both GM and WM. These relationships were independent of a number of potential confounders, including age, sex, puberty stage, household income and height. Our results suggest that both visceral fat and fat deposited elsewhere in the body are associated independently with structural properties of the adolescent brain. We speculate that these relationships suggest the presence of adiposity-related variations in phospholipid composition of brain lipids.

Highlights • Psychiatric conditions contribute the most to global health burden. • Developmental cascades provide a framework for understanding causes and consequences. • Multi-generational design enables studies of virtual health trajectories. • Saguenay Youth Study is a multi-generational and multi-system cohort designed along these lines., This paper provides an overview of the Saguenay Youth Study (SYS) and its parental arm. The overarching goal of this effort is to develop trans-generational models of developmental cascades contributing to the emergence of common chronic disorders, such as depression, addictions, dementia and cardio-metabolic diseases. Over the past 10 years, we have acquired detailed brain and cardio-metabolic phenotypes, and genome-wide genotypes, in 1029 adolescents recruited in a population with a known genetic founder effect. At present, we are extending this dataset to acquire comparable phenotypes and genotypes in the biological parents of these individuals. After providing conceptual background for this work (transactions across time, systems and organs), we describe briefly the tools employed in the adolescent arm of this cohort and highlight some of the initial accomplishments. We then outline in detail the phenotyping protocol used to acquire comparable data in the parents.

Some of the known sex differences in white matter emerge during adolescence. Here, we replicate and extend our previous findings of sex differences in the structure of the corticospinal tract (Perrin et al. 2009; Herve et al. 2009). In a large normative sample of adolescents, we observed age × sex interactions in the signal intensity of T1-weighted (T1W) images (n = 941) and in magnetization transfer ratio (MTR; n = 761); both features were inversely associated with age in males but not in females. Moreover, we hypothesized that the age-related differences in CST structure exhibited by males would be mediated by differences in puberty stage and levels of bioavailable testosterone. We confirmed this prediction using mediation analysis with bootstrapping. These findings suggest that sex differences in the CST structure observed during male adolescence may be due to multiple processes associated with puberty, including (but not limited to) the rising levels of testosterone.

This review focuses on the maturation of brain white-matter, as revealed by magnetic resonance (MR) imaging carried out in healthy subjects. The review begins with a brief description of the nature of the MR signal and its possible biological underpinnings, and proceeds with a description of MR findings obtained in newborns, infants, children and adolescents. On MR images, a significant decrease in water content leads to a decrease of longitudinal relaxation times (T1) and transverse relaxation times (T2) and consequent “adult-like” appearance of T1-weighted and T2-weighted images becomes evident towards the end of the first year of life. Owing to the onset of myelination and the related increase of lipid content, MR images gradually acquire an exquisite grey-white matter contrast in a temporal sequence reflecting the time course of myelination. Albeit less pronounced, age-related changes in white matter continue during childhood and adolescence; white matter increases its overall volume and becomes more myelinated in a region-specific fashion. Detection of more subtle changes during this “late” phase of brain development is greatly aided by computational analyses of MR images. The review also briefly outlines future directions, including the use of novel MR techniques such as diffusion tensor imaging and magnetization transfer, as well as the suggestion for the concurrent use of experimental behavioral test-batteries, with structural MR imaging, to study developmental changes in structure-function relationships.

The pituitary gland is a key structure in the hypothalamic-pituitary-gonadal (HPG) axis--it plays an important role in sexual maturation during puberty. Despite its small size, its volume can be quantified using magnetic resonance imaging (MRI). Here, we study a cohort of 962 typically developing adolescents from the Saguenay Youth Study and estimate pituitary volumes using a newly developed multi-atlas segmentation method known as the MAGeT Brain algorithm. We found that age and puberty stage (controlled for age) each predicts adjusted pituitary volumes (controlled for total brain volume) in both males and females. Controlling for the effects of age and puberty stage, total testosterone and estradiol levels also predict adjusted pituitary volumes in males and pre-menarche females, respectively. These findings demonstrate that the pituitary gland grows during adolescence, and its volume relates to circulating plasma-levels of sex steroids in both males and females.

Prenatal exposure to maternal cigarette smoking interacts with a polymorphism in the α6 nicotinic acetylcholine receptor gene to influence drug use and striatum volume in adolescence

Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.We used data obtained in two geographically distinct community samples of adolescents. The first (cross-sectional) sample consisted of 996 adolescents (12-18 years of age) recruited from the Saguenay Youth Study (SYS) in Canada (47% with PEMCS). The second (longitudinal) sample consisted of 1141 adolescents (49% with PEMCS) from the Northern Finland Birth Cohort (NFBC1986). In both samples, externalizing behavior and substance use were assessed during adolescence. In the NFBC1986 cohort, externalizing behavior was also assessed in childhood.In both populations, PEMCS is associated with a higher likelihood of adolescent drug experimentation. In the NFBC1986 cohort, exposed (versus non-exposed) adolescents experiment with an extra 1.27 [B = 0.24, 95% confidence intervals (CI) = 0.15, 0.33 P 0.001] drugs. In the SYS cohort, a clear protective effect of not being exposed is shown: non-exposed (versus exposed) adolescents are 1.5 times [B = -0.42, 95% CI = -0.75, -0.09, P = 0.013] less likely to take drugs. These associations between PEMCS and drug experimentation remain in the multivariate and mediational analyses.Prenatal exposure to maternal cigarette smoking appears to be associated with a higher probability of experimenting with drugs during adolescence, both directly and indirectly via externalizing behavior and the number of peers reported as using drugs.

Objective : Visceral fat (VF) increases cardiometabolic risk more than fat stored subcutaneously. Here, we investigated how well routine clinical measures of adiposity, namely body mass index (BMI) and waist circumference (waist), predict VF and subcutaneous fat (SF) in a large population-based sample of adolescents. As body-fat distribution differs between males and females, we performed these analyses separately in each sex. Design and Methods : VF and SF were measured by magnetic resonance imaging in 1,002 adolescents (482 males, age 12–18 years). Relationships of BMI and waist with VF and SF were tested in multivariable analyses, which adjusted for potentially confounding effects of age and height. Results : In both males and females, BMI and waist were highly correlated with VF and SF, and explained 55–76% of their total variance. When VF was adjusted for SF, however, BMI and waist explained, respectively, only 0% and 4% of VF variance in males, and 4% and 11% of VF variance in females. In contrast, when SF was adjusted for VF, BMI and waist explained, respectively, 36% and 21% of SF variance in males, and 48% and 23% of SF variance in females. These relationships were similar during early and late puberty. Conclusions and Relevance : During adolescence, routine clinical measures of adiposity predict well SF but not VF. This holds for both sexes and throughout puberty. Further longitudinal studies are required to assess how well these measures predict changes of VF and SF over time. Given the clinical importance of VF, development of cost-effective imaging techniques and/or robust biomarkers of VF accumulation that would be suitable in everyday clinical practice is warranted.

In our previous work, we described facial features associated with a successful recognition of the sex of the face ( Mareckova et al., 2011 ). These features were based on landmarks placed on the surface of faces reconstructed from magnetic resonance (MR) images; their position was therefore influenced by both soft tissue (fat and muscle) and bone structure of the skull. Here, we ask whether bone structure has dissociable influences on observers' identification of the sex of the face. To answer this question, we used a novel method of studying skull morphology using MR images and explored the relationship between skull features, facial features, and sex recognition in a large sample of adolescents (n = 876; including 475 adolescents from our original report). To determine whether skull features mediate the relationship between facial features and identification accuracy, we performed mediation analysis using bootstrapping. In males, skull features mediated fully the relationship between facial features and sex judgments. In females, the skull mediated this relationship only after adjusting facial features for the amount of body fat (estimated with bioimpedance). While body fat had a very slight positive influence on correct sex judgments about male faces, there was a robust negative influence of body fat on the correct sex judgments about female faces. Overall, these results suggest that craniofacial bone structure is essential for correct sex judgments about a male face. In females, body fat influences negatively the accuracy of sex judgments, and craniofacial bone structure alone cannot explain the relationship between facial features and identification of a face as female.

International audience; BACKGROUND:The purpose of this investigation was to evaluate an association between duration of exclusive breastfeeding and structure of cortical regions implicated in general intelligence.METHODS:We studied adolescents (n = 571; aged 12-18 years) participating in the Saguenay Youth Study; half of the participants were exposed to maternal cigarette smoking during pregnancy. Hierarchical linear modelling was used to assess whether breastfeeding is an important predictor of cortical thickness when other predictors, such as age, sex, parental education and exposure to maternal smoking during pregnancy, are also considered. Target cortical regions were identified using a meta-analysis of functional neuroimaging studies of cognitive abilities relevant for general intelligence.RESULTS:We found that duration of exclusive breastfeeding was associated with cortical thickness in the superior and inferior parietal lobules (t = 2.31, P = 0.02). We also replicated the association between breastfeeding and general intelligence (t = 2.69, P = 0.008).CONCLUSION:In this study, we showed that breastfeeding is associated with variations in the thickness of the parietal cortex in a community-based sample of adolescents. We also found association of breastfeeding duration with full scale and performance IQ, as observed previously.

Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10(-6). These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.

It is important to account for timing of puberty when studying the adolescent brain and cognition. The use of classical methods for assessing pubertal status may not be feasible in some studies, especially in male adolescents. Using data from a sample of 478 males from a longitudinal birth cohort, we describe the calculations of three independent height-based markers of pubertal timing: Age at Peak Height Velocity (APHV), Height Difference in Standard Deviations (HDSDS), and Percent Achieved of Adult Stature (PAAS). These markers correlate well with each other. In a separate cross-sectional study, we show that the PAAS marker correlates well with testosterone levels and self-reported pubertal-stage scores. We conclude by discussing key considerations for investigators when drawing upon these methods of assessing pubertal timing.

Intracarotid injection of sodium amytal barbiturate was administered to a right-handed patient of low average intelligence with agenesis of the corpus callosum (as revealed by MRI). Injection into the left cerebral hemisphere produced speech arrest and dysphasia; injection into the right did not result in language disturbance. Several authors have argued that the corpus callosum plays a critical role in the normal progression of cerebral lateralization, providing a pathway by which the right hemisphere can be inhibited to suppress language development. This hypothesis is not supported by our findings, which furnish unequivocal documentation of unilateral language lateralization in the absence of the corpus callosum and support the conclusion that this interhemispheric commissure is not crucial to unilateral hemispheric language development.

Monkeys with unilateral principal sulcus (PS) lesions show a contralateral deficit in localizing remembered targets, especially as the recall interval is lengthened. We tested 20 patients with unilateral frontal-lobe excisions that invaded (FI) or spared (FS) area 46 (putative homologue of PS) and 32 normal controls (NC) on a task where subjects had to indicate the location of a light dot either immediately, or after 30 s, with or without interference. The FI group was worse than the NC group following both delay conditions. NC and FS groups differed only after interference. We concluded that area 46 is involved in recalling the location of visual targets, but unlike the monkey, the deficit is not restricted to a particular part of the visual field.

In previous work, Leonard and Milner (Neuropsychologia, 29, 47-58, 1991) demonstrated that patients with large excisions from the right frontal lobe have difficulty in reproducing accurately the extent of examiner-defined arm movements, the displacements being made without the aid of vision. The impairment in the right frontal-lobe group was not dependent on recall-condition, being apparent irrespective of the presence of a delay, suggesting that the deficit was primarily one of encoding. We then went on to show that these same patients have a short-term memory deficit when recalling terminal position of examiner-defined arm movements (Neuropsychologia 29, 629-640, 1991). From these investigations we concluded that the right frontal lobe is critically involved in the monitoring of information related to movement. In the present study 58 patients with unilateral temporal- or frontal-lobe excisions were tested on two kinesthetic tasks that required the subjects themselves to select terminal positions, or movement extents, thereby reducing dependence on peripheral feedback. Patients with right frontal-lobe lesions could reproduce these self-generated movements normally, indicating that when demands on feedback are reduced the frontal-lobe contribution is not critical.

International audience; The most dramatic growth of the human brain occurs in utero and during the first 2 years of postnatal life. Genesis of the cerebral cortex involves cell proliferation, migration, and apoptosis, all of which may be influenced by prenatal environment. Here, we show that variation in KCTD8 (potassium channel tetramerization domain 8) is associated with brain size in female adolescents (rs716890, P 5 5.40 3 10 209). Furthermore, we found that the KCTD8 locus interacts with prenatal exposure to maternal cigarette smoking visa `-vis cortical area and cortical folding: In exposed girls only, the KCTD8 locus explains up to 21% of variance. Using head circumference as a proxy of brain size at 7 years of age, we have replicated this gene-environment interaction in an independent sample. We speculate that KCTD8 might modulate adverse effects of smoking during pregnancy on brain development via apoptosis triggered by low intracellular levels of potassium, possibly reducing the number of progenitor cells.

Greater blood pressure (BP) reactivity and slower BP recovery from physical and mental challenges predict future hypertension. Males exhibit higher BP than females throughout their reproductive age and, as such, have a higher prevalence of hypertension. Excess body-fat is a major risk factor for hypertension in both males and females. We investigated whether BP reactivity and recovery from physical and mental challenges differ between adolescent males and females, and whether these hemodynamic parameters are associated with resting BP and are influenced by excess body-fat in a sex-specific manner. In 285 male and 311 female adolescents (age 12-18 years), we quantified visceral fat (VF) with magnetic resonance imaging and total body fat (TBF) with bioimpedance and measured systolic BP (SBP) beat-by-beat at rest and during physical (10-min standing) and mental (2-min math test) challenges. Our results showed that in both sexes, BP reactivity and BP recovery for both challenges (adjusted for age, height and initial BP) correlated closely with resting BP (0.03 ≤ r2 ≤ 0.34). In addition, for both physical and mental challenges, males versus females showed greater BP reactivity (by 3.5 mm Hg, p

Individuals who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges at a young age are at increased risk of developing hypertension in adulthood. Hypertension is a complex genetic trait that is more prevalent in men than women during reproductive age. CYP17A1 is one of the best-established gene loci of hypertension. It encodes a key enzyme in the steroidogenic pathway that produces mineralocorticoids, glucocorticoids, androgens, and estrogens; as such, it may influence BP reactivity in a sex-specific manner. Here, we investigated whether CYP17A1 is associated with BP reactivity to physical and mental challenges in adolescence. In 285 male and 311 female adolescents (age 12-18 years), we measured systolic BP (SBP) and diastolic BP (DBP) beat-by-beat during a 52-minute protocol, which included a physical (10-min standing) and mental (2-min math test) challenge and we genotyped 8 tagging single nucleotide polymorphisms (SNPs) that covered the entire region of CYP17A1. Genotype-phenotype association tests were performed separately in males and females, while adjusting for age, height and initial BP. Our results showed that 6 SNPs were associated with higher SBP and DBP reactivity (p=0.003-0.0001), but only in response to mental stress and only in boys. At rs619824 , minor allele homozygotes differed from major allele homozygotes by 8.7 mm Hg of SBP (p=3x10-4) and 4.8 mm Hg of DBP (p=1x10-4) in boys, and the two groups varied only by 2.0 mm Hg of SBP (p=0.31) and 0.9 mm Hg of DBP (p=0.42) in girls. These results suggest that CYP17A1 may contribute to the development of hypertension through the regulation of the stress response and that, at least in adolescence, this effect appears to be present in males but not in females.

Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the μ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10(-6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume.

This study investigated the fine-grained development of the EEG power spectra in early adolescence, and the extent to which it is reflected in changes in peak frequency. It also sought to determine whether sex differences in the EEG power spectra reflect differential patterns of maturation. A group of 56 adolescents were tested at age 10 years and then at two further time-points approximately 18 months apart. The EEG was recorded during both eyes-closed and eyes-open conditions and Fourier transformed to provide estimates of absolute and relative spectral power at 0.5 Hz intervals from 0.5 to 40 Hz. The peak alpha frequency for each individual at each time-point was also determined for relative spectral power. Partial Least Squares (PLS) analysis was used to determine the combination of electrodes and frequencies that showed developmental change, or differed between the sexes. As a function of age, absolute delta and theta frequencies power decreased, and relative alpha2 and beta frequencies increased, replicating the standard findings of a decrease in lower, and increase in higher, frequencies with age. A small but significant increase in peak alpha frequency with age was detected. Moreover PLS analysis performed with individual alpha frequencies aligned to 10 Hz suggested that the age-related increase seen in alpha2 relative power was driven by changes in the peak frequency. Although males demonstrated higher alpha power than females, there were no sex differences in peak frequency, suggesting that there may be more to sex differences in EEG power than simply different rates of maturation between the two sexes.

Quantitative analysis of craniofacial morphology is of interest to scholars working in a wide variety of disciplines, such as anthropology, developmental biology, and medicine. T1-weighted (anatomical) magnetic resonance images (MRI) provide excellent contrast between soft tissues. Given its three-dimensional nature, MRI represents an ideal imaging modality for the analysis of craniofacial structure in living individuals. Here we describe how T1-weighted MR images, acquired to examine brain anatomy, can also be used to analyze facial features. Using a sample of typically developing adolescents from the Saguenay Youth Study (N = 597; 292 male, 305 female, ages: 12 to 18 years), we quantified inter-individual variations in craniofacial structure in two ways. First, we adapted existing nonlinear registration-based morphological techniques to generate iteratively a group-wise population average of craniofacial features. The nonlinear transformations were used to map the craniofacial structure of each individual to the population average. Using voxel-wise measures of expansion and contraction, we then examined the effects of sex and age on inter-individual variations in facial features. Second, we employed a landmark-based approach to quantify variations in face surfaces. This approach involves: (a) placing 56 landmarks (forehead, nose, lips, jaw-line, cheekbones, and eyes) on a surface representation of the MRI-based group average; (b) warping the landmarks to the individual faces using the inverse nonlinear transformation estimated for each person; and (3) using a principal components analysis (PCA) of the warped landmarks to identify facial features (i.e. clusters of landmarks) that vary in our sample in a correlated fashion. As with the voxel-wise analysis of the deformation fields, we examined the effects of sex and age on the PCA-derived spatial relationships between facial features. Both methods demonstrated significant sexual dimorphism in craniofacial structure in areas such as the chin, mandible, lips, and nose.

This chapter talks about Mary who was admitted to Tertiary Hospital in early June of 2003 having stumbled to the ground being unable to get up. CT of her head confirmed general parenchymal volume loss with decreased attenuation periventricularly. No significant areas of ischemia or space-occupying lesions were noted. PET scan was suggestive of a neurodegenerative process of Alzheimer's type. No scan evidence of frontal lobe dementia. The diagnosis prior to the PET scan being performed was frontotemporal dementia. The final clinical diagnosis after the PET scan and on discharge was that of Alzheimer's type dementia. She was not started on acetylcholine esterase therapy. She was discharged to a low level residential facility. This case is interesting in that it does not on face value fit into one category of neurodegenerative disorders. False beliefs related to misinterpretation of the environment due to significant visual impairment is known as Charles-Bonnet syndrome.

Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with variations in brain and behavior in adolescence. Epigenetic mechanisms may mediate some of the consequences of PEMCS through methylation of deoxyribonucleic acid (DNA) in genes important for brain development, such as the brain-derived neurotrophic factor (BDNF). In the current study, we used bisulfite sequencing to assess DNA methylation of the BDNF promoter in the blood of adolescents whose mothers smoked during pregnancy. We demonstrate that PEMCS is associated with higher rates of DNA methylation in the BDNF-6 exon. These results suggest that PEMCS may lead to long-term down-regulation of BDNF expression via the increase of DNA methylation in its promoter region. Such mechanisms could, in turn, lead to modifications in both development and plasticity of the brain exposed in utero to maternal cigarette smoking.

Context : Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring. Objective : To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use. Design : Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level. Participants and Setting : A French Canadian founder population of the Saguenay–Lac-Saint-Jean region of Quebec, Canada.The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents. Main Outcome Measures : The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software. Results : Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met). Conclusions : We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.

Objectives To investigate during adolescence (1) sex differences in blood pressure (BP) and hemodynamic factors at rest and during physical and mental challenges and (2) whether these differences are mediated by body composition and glucose and lipid metabolism. Design Cross-sectional study of a population-based cohort. Setting Saguenay Youth Study, Quebec, Canada, from November 2003 to June 2007. Participants A total of 425 adolescents (225 girls aged 12-18 years). Outcome Measures Systolic and diastolic BP measured using a Finometer. Secondary outcome measures were (1) hemodynamic parameters also measured with a Finometer, (2) body composition assessed with magnetic resonance imaging, bioimpedance, and anthropometry, and (3) metabolic indices determined from a fasting blood sample. Results Girls vs boys demonstrated lower systolic and diastolic BP at rest and during challenges, with the differences being greatest during a math-stress test (adjusted difference, 7 mm Hg; 95% confidence interval [CI], 4-10 mm Hg and adjusted difference, 6 mm Hg; 95% CI, 4-8 mm Hg, respectively). The differences were mainly due to girls vs boys having lower stroke volume while lying down, standing (adjusted difference, 4 mL; 95% CI, 1-7 mL), and sitting, and lower total peripheral resistance during the math-stress test (adjusted difference, 0.14 mm Hg · s/mL; 95% CI, 0.09-0.21 mm Hg · s/mL). Intra-abdominal fat was positively associated with BP, but less in girls than in boys, and fat-free mass, fat mass, and insulin resistance were also positively associated with BP, similarly in boys and girls. Conclusions In adolescence, BP is lower in girls than boys, with the difference being determined mainly by lower stroke volume during physical challenges and by lower total peripheral resistance during mental challenges. Body composition and insulin resistance contribute to these differences.

International audience; A common Single-Nucleotide Polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) gene coding the Val66Met substitution in the pro-BDNF protein has been associated with a number of behavioural and neuroanatomical phenotypes; the latter include, for example, regional differences in volumes of the hippocampus and prefrontal grey matter. Here, we show that the observed regional differences may not stem from a localised effect of this gene. Our analysis of regional brain volume in a cohort of 331 adolescents indicates that the Val66Met substitution has a global effect on brain volume, and that the observed local differences are to be expected if brain allometry-the covariance pattern of regional brain volumes-is taken into account.

A retrospective study of 383 patients who had undergone either left or right anterior temporal lobectomy (varying with respect to the amount of hippocampus excised) revealed that there were no significant differences in surgical outcome between those patients having a large and those patients having a small hippocampal removal. Although left temporal-lobe excisions were significantly smaller than right temporal-lobe excisions, both medially and laterally, patients with left temporal-lobe removals had an overall better surgical outcome. Patients in the successful surgicaloutcome group did better than the unsuccessful surgical-outcome group on a variety of cognitive measures, including tests of intelligence, delayed verbal memory, and verbal fluency. The results suggest that, for many patients with medically intractable epilepsy, an anterior temporal lobectomy including the amygdala may suffice to reduce their seizure frequency.

Three recency-discrimination tasks (involving concrete words, representational drawings and abstract paintings) were administered to 117 patients who had undergone unilateral cortical removals, and to 20 normal control subjects. Frontal or anterior temporal-lobe excision did not impair simple item recognition, and neither left nor right anterior-temporal lobectomy affected recency judgements on any task. In contrast, excisions that encroached on the mid-lateral frontal cortex impaired verbal recency judgements, the deficit being mild after right frontal lobectomy. Patients with right frontal-lobe removals showed the greatest impairment in recency discrimination on the two pictorial tests. The results provide evidence for hemispheric specialization related to the nature of the stimulus material and some support for a functional role for the left mid-lateral frontal cortex in verbal recency judgements.

BACKGROUND The incidence of cigarette smoking during pregnancy remains high. Maternal smoking during pregnancy is known to be associated with cognitive and behavioural sequelae in childhood and adolescence. We assessed the relationship between maternal cigarette smoking during pregnancy and cognitive abilities in adolescent offspring (n = 503, 12- to 18-years old) using an extensive 6-h battery of tests. METHODS Non-exposed adolescents (controls) were matched to exposed adolescents (cases) by maternal education and school attended. Cognitive abilities were evaluated using a neuropsychological battery consisting of 33 tasks measuring verbal abilities, visuo-spatial skills, verbal and visual memory, processing speed, resistance to interference and motor dexterity. RESULTS We found no differences between cases and controls in any of the cognitive domains whether potential confounders were included in the model or not. In addition to maternal smoking during pregnancy, we also evaluated the effect of sex and age on the various cognitive abilities in this large adolescent sample and found that most of the abilities continue to improve during adolescence to the same extent in girls and boys, with several age-independent sex differences. CONCLUSIONS We found no effect of maternal cigarette smoking during pregnancy on cognitive abilities of the adolescent offspring when matching cases and controls by maternal education, the most common confounder of maternal cigarette smoking during pregnancy.

Children with high resistance to peer influences differ from their low-resistance counterparts in the degree of functional connectivity in fronto-parietal and prefrontal cortical networks. Here we explored the possibility that the degree of morphological similarities across the same cortical regions also varies as a function of this behavioral trait. Using structural magnetic-resonance (MR) images, we measured cortical thickness in a total of 295 adolescents (12 to 18 years of age). We found that inter-regional correlations in cortical thickness increased with the resistance to peer influence (RPI); this was especially the case, in female adolescents, in the premotor and prefrontal networks. We also observed significant differences between the adolescents with high and low RPI scores in their general intelligence and the scores of positive youth development. We suggest that these morphological findings might reflect differences, between adolescents with high vs. low resistance to peer influences, in a repeated and concurrent engagement of these networks in social context.

The growth of white matter during human adolescence shows a striking sexual dimorphism; the volume of white matter increases with age slightly in girls and steeply in boys. Here, we provide evidence supporting the role of androgen receptor (AR) in mediating the effect of testosterone on white matter. In a large sample of typically developing adolescents (n= 408, 204 males), we used magnetic resonance imaging and acquired T1-weighted and magnetization transfer ratio (MTR) images. We also measured plasma levels of testosterone and genotyped a functional polymorphism in the AR gene, namely the number of CAG repeats in exon 1 believed to be inversely proportional to the AR transcriptional activity. We found that the testosterone-related increase of white-matter volume was stronger in male adolescents with the lower versus higher number of CAG repeats in the AR gene, with testosterone explaining, respectively, 26 and 8% of variance in the volume. The MTR results suggest that this growth is not related to myelination; the MTR decreased with age in male adolescents. We speculate that testosterone affects axonal caliber rather than the thickness of the myelin sheath.

To investigate the association between intra-abdominal adiposity and individual components of the metabolic syndrome (MS) in adolescent males and females.Cross-sectional study of a population-based cohort.Saguenay Youth Study, Quebec, Canada.A total of 324 adolescents, aged 12 to 18 years.Measures were compared between males and females with "high" or "low" intra-abdominal fat (IAF).Intra-abdominal fat was quantified with magnetic resonance imaging. Primary outcome measures were blood pressure (BP) and fasting serum glucose, insulin, lipids, and C-reactive protein levels. Secondary mechanistic measures were cardiovascular variability indexes of autonomic nervous system function, pubertal development, and serum levels of cortisol, leptin, and sex hormones.The MS was completely absent in adolescents with low IAF and was present in 13.8% of males and 8.3% of females with high IAF. Excess IAF was associated with a higher homeostasis model assessment index (0.5 [95% confidence interval (CI), 0.3 to 0.8]; P.001) and triglycerides level (17.7 mg/dL [to convert to millimoles per liter, multiply by 0.0113] [95% CI, 9.7 to 25.7 mg/dL]; P.001), lower high-density lipoprotein cholesterol level (-3.9 mg/dL [to convert to millimoles per liter, multiply by 0.0259] [95% CI, -6.2 to -1.5 mg/dL]; P = .003), and higher C-reactive protein level (0.03 mg/L [to convert to nanomoles per liter, multiply by 9.524] [95% CI, 0.01 to 0.05 mg/L]; P = .003). High IAF was associated with elevations of BP and sympathetic activity in males only (higher systolic BP, 6 mm Hg [95% CI, 1 to 11 mm Hg]; P = .02 and low-frequency power of diastolic BP, 629 mm Hg2 [95% CI, 37 to 1222 mm Hg2]; P = .04).Our results suggest that, already in adolescence, accumulation of IAF may promote development of the MS, affecting the metabolic and inflammatory components similarly in both sexes but influencing BP adversely only in males. The latter may be attributed, in part, to the augmentation of sympathetic activity also seen only in males.

Mucopolysaccharidosis type IIID (MPS-IIID), or Sanfilippo syndrome type D, is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetylglucosamine-6-sulfatase (GNS) gene, leading to impaired degradation of heparan sulfate.To report the natural history of MPS-IIID in 2 siblings described by Kaplan and Wolfe in 1987 and to study the phenotype in 2 other unrelated families with MPS-IIID. Design, Setting, and Patients Case series of 4 patients with MPS-IIID: 2 siblings followed up at the Montreal Neurological Hospital and Institute, 1 patient followed up at the UZ Brussel, and 1 patient recruited through the prenatal counseling program at the UZ Brussel.Clinical and molecular data collected from 3 families with enzyme-based diagnosis of MPS-IIID.The course of the disease was characteristic of MPS-IIID in all patients, although survival may be longer than was previously reported. In family 1, both siblings were homozygous for a novel nonsense mutation in the GNS gene (c.1168CT). In family 2, the proband carried a heterozygous mutation occurring in a splice recognition site in the intron 7 boundary (c.876-2AG). The second mutation in this patient remains to be identified. In family 3, the proband was homozygous for a novel frameshift mutation in GNS due to the insertion of 5 nucleotides (c.1138_1139insGTCCT).Major issues in the care of patients with MPS-IIID include behavioral problems, sleep problems, recurrent infections, dysphagia, and pain from orthopedic complications. To date, all mutations in GNS predict protein truncation, and there is no obvious genotype-phenotype correlation.

Smoking during pregnancy is associated with long-term consequences on offspring behavior. We measured thickness of the cerebral cortex using magnetic resonance images obtained in 155 adolescents exposed in utero to maternal smoking and compared them with 159 non-exposed subjects matched by maternal education. Orbitofrontal, middle frontal, and parahippocampal cortices were thinner in exposed, as compared with non-exposed, individuals; these differences were more pronounced in female adolescents. In exposed females, the thickness of the orbitofrontal cortex correlated negatively with a self-rated assessment of caring, one of the components of a model of positive youth development. These findings provide evidence of the long-term impact of prenatal environment on a neural substrate of cognition and social behavior.

The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large-scale study of gene-environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long-term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individual's response to an in utero environment (i.e. PEMCS), the study is family-based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac-Saint-Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome-wide scan will be carried out with sib-pair linkage analyses, and fine mapping of identified loci will be done with family-based association analyses. Adolescent sibships (12-18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French-Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer-based neuropsychological tests, (3) hospital-based cardiovascular, body-composition and metabolic assessments, and (4) questionnaire-derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home-environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI-based assessment of familiality in the brain size and the volumes of grey and white matter.

IMPORTANCE: Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure. OBJECTIVE: To evaluate whether the association between cannabis use and cortical maturation in adolescents is moderated by a polygenic risk score for schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Observation of 3 population-based samples included initial analysis in 1024 adolescents of both sexes from the Canadian Saguenay Youth Study (SYS) and follow-up in 426 adolescents of both sexes from the IMAGEN Study from 8 European cities and 504 male youth from the Avon Longitudinal Study of Parents and Children (ALSPAC) based in England. A total of 1577 participants (aged 12-21 years; 899 [57.0%] male) had (1) information about cannabis use; (2) imaging studies of the brain; and (3) a polygenic risk score for schizophrenia across 108 genetic loci identified by the Psychiatric Genomics Consortium. Data analysis was performed from March 1 through December 31, 2014. MAIN OUTCOMES AND MEASURES: Cortical thickness derived from T1-weighted magnetic resonance images. Linear regression tests were used to assess the relationships between cannabis use, cortical thickness, and risk score. RESULTS: Across the 3 samples of 1574 participants, a negative association was observed between cannabis use in early adolescence and cortical thickness in male participants with a high polygenic risk score. This observation was not the case for low-risk male participants or for the low- or high-risk female participants. Thus, in SYS male participants, cannabis use interacted with risk score vis-à-vis cortical thickness (P = .009); higher scores were associated with lower thickness only in males who used cannabis. Similarly, in the IMAGEN male participants, cannabis use interacted with increased risk score vis-à-vis a change in decreasing cortical thickness from 14.5 to 18.5 years of age (t137 = -2.36; P = .02). Finally, in the ALSPAC high-risk group of male participants, those who used cannabis most frequently (≥61 occasions) had lower cortical thickness than those who never used cannabis (difference in cortical thickness, 0.07 [95% CI, 0.01-0.12]; P = .02) and those with light use (