The obtained model contains only the second-order Kier and Hall molecular connectivity index. It is suggested that the index 2χ includes some information about flexibility. The obtained model was used to predict log10 cmc of other cationic gemini surfactants. The agreement between calculated and experimental values of log10 cmc for the gemini surfactants that were not used in the correlation is very good.Modelling of the critical micelle concentrations ( The cmc values of these surfactants are significantly lower than those of the corresponding monomeric surfactants and in comparison to their monomeric counterparts, gemini surfactants are more efficient at reducing surface tension. Gemini surfactants demonstrate great potential for gene delivery  with a given alkyl chain, particularly for the series with m = 12, increases with the spacer length up to a maximum at four or five methylene units and then decrease with further increase in the number of methylene units in the spacer group [cmc values of dissymmetric surfactants designated as m–6–6 are about one order of magnitude higher than those of the corresponding m–6–m symmetric surfactants [cmc decreases as the m/n ratio increases. In the case of the dissymmetric surfactants designated as m–6–n with m + n = 24, the cmc values are comparable with those of the symmetric counterparts with m = 12 [cmc slightly decreases as the m/n ratio increases. The cmc values of m–7NH–m -1,1,9,9-tetramethyl-5-imino-1,9-nonanediammonium dibromide) [m–7–m gemini surfactants [cmc values of (CnN)2(OH)2 -2,3-butanediol) [N,N-dimethylammonium bromide)-2-butanol) [cmc decreases with increasing hydroxyl substitution in the spacer [The er group , 17. Thefactants  and the h m = 12  and the bromide) , 21 gemifactants  whereas anediol) , 23 and 10 cmc are given in Table cmc values were measured at 25.00 °C.Literature data for logm is the order of the connectivity index, k denotes the type of a fragment, which is divided into paths (P), clusters (C), and path/clusters (PC). In formula nm is the number of relevant paths and δi is the connectivity degree and is equal to the number of atoms to which the i-th atom is bonded. If we replace δi by m-th order valence molecular connectivity index is as follows:Zν is the number of valence electrons in the corresponding atom, h is the number of hydrogen atoms connected to the i-th atom and Z is the atomic number.Molecular connectivity indices, some of the topological descriptors to characterize molecules in structure–property and structure–activity studies, were originally proposed by Randic  and late2χ index are given in Appendices An example of calculations of molecular connectivity indices for exemplary gemini surfactant and some useful information about the 10 cmc and the molecular connectivity indices was generated using the least-squares method. The statistical calculations were performed using the program STATISTICA 9.1 [r), a Fisher ratio value (F) and a standard error (s). The best relationship is that which has possibly highest values of r and F, and simultaneously the lowest value of s.Modelling of the critical micelle concentration as a function of molecular connectivity indices was performed for a diverse set of 21 gemini surfactants. The formula expressing the relationship between the logTICA 9.1 . In the 10 cmc values are listed in Table The aim of the present work is to find the simple equation expressing the critical micelle concentration of cationic gemini surfactants as a function of the molecular connectivity indices only. In the process of searching for the simple relationship were used, just as in the previous papers , 12, tenJust as in the previous papers we started our correlation procedure with one index. This step is presented in Table 2χ, and we get the following formula:We see that the best correlation in this step is for the relationship containing the second-order connectivity index Next to this index we added the remaining indices separately. The values of the correlation coefficients for second step are shown in Table The addition of other indices in the second step did not change significantly the correlation coefficient and other parameters; therefore at first step the process of searching for the best relationship was ended.10 cmc with those calculated from Eq. The comparison between the experimental values of log10 cmc using the obtained model , and the experimental values of cmc are the following: 51, 6, 1.09, 0.15, 0.03 (mmol·L−1) [mN)2(OH)2 with m = 10, 12, 14, 16 we obtain the following values of index 2χ: 13.141, 14.555, 15.969, 17.384 and calculated values of cmc: 3.30, 0.67, 0.14, 0.03 (mmol·L−1), and the experimental values of cmc are the following: 3.7, 0.7, 0.085, 0.05 (mmol·L−1) [cmc with increasing alkyl chain length is also observed. Next, when the number of methylene groups increases in the spacer group and in consequence the values of index 2χ increase, then the experimental and also the calculated values of cmc decrease. For example, for the compounds 12–s–12 with s = 4, 6, 7 we obtain the following values of index 2χ: 13.399, 14.107, 14.460 and calculated values of cmc: 2.47, 1.11, 0.74 (mmol·L−1) and the experimental values of cmc are the following: 1.17, 1.09, 0.9 (mmol·L−1) [cmc decrease with increasing hydroxyl substitution in the spacer and the values of index 2χ increase also. For example, for the compounds 12–4(OH)n–12 with n = 0, 1, 2 we obtain the following values of index 2χ: 13.399, 14.04, 14.555 and calculated values of cmc: 2.47, 1.20, 0.67 (mmol·L−1) and the experimental values of cmc are the following: 1.17, 0.94, 0.7 (mmol·L−1) [Inspection of the data in Tables mol·L−1) , 26, andmol·L−1) , respectmol·L−1) , respectcmc decrease with increasing number of methylene groups or hydroxyl substitution in the spacer. For 12–s–12 gemini surfactants, as the spacer increases in length it becomes more flexible [n–12 gemini surfactants, the increase in hydroxyl substitutions in the spacer group may also cause the increase in the flexibility of that group [2χ increases then the cmc decreases. This may suggest that the index 2χ includes some information about the flexibility of that group.If we take into account only the spacer group we can see that for given gemini surfactants the experimental values of flexible . In the at group . From th10 cmc for some other cationic gemini surfactants to test Eq. The obtained model was used to predict log10 cmc for the cationic gemini surfactants which were not used in the correlation is very good.As shown in Table 12N)2(OH)2, we obtain the following values of index 2χ: 14.107, 14.375, 14.555, the following calculated values of cmc: 1.11, 0.82, 0.67 (mmol·L−1), and the experimental values of cmc are the following: 1.09, 0.97, 0.7 (mmol·L−1) [The data contained in Tables mol·L−1) , 21, 22,cmc decreases. This refers not only to the spacer group but also to the whole molecule and is in agreement with some experimental and also theoretical results obtained for conventional surfactants [2χ index, appearing in the model, includes some information about flexibility.From the obtained relationship, it follows that when the number of atoms and/or the number of branches increase in the spacer group then the factants , 15. Thecmc of cationic gemini surfactants especially bis-quaternary ammonium bromide salts with medium-length spacers and can be helpful in designing novel cationic gemini surfactants.The results obtained for the compounds taken into consideration Tables , 5 show


Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.Children (6–12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.Z = 3.74, P = 0.0002), behavioral assessments by parents , as well as restless-impulsive subscale scores on Conners’-teachers (P = 0.006) and parents (P = 0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff , parents , as well as evaluation in the simulated academic environment .A highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis ; www.clinicaltrials.gov; NCT00483106.By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within  Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent psychiatric disorder, with rates ranging from 5.9–7.1% in children and adolescents Psychostimulants, mostly methylphenidate (MPH) SLC6A2 which has been mapped to 16 q12.2. SLC6A2 as a candidate in genetic and pharmacogenetic studies of ADHD. Importance of the NE transporter has been further emphasized since it is responsible for the reuptake of both NE and DA in the prefrontal cortex (PFC), a brain region critical for attention regulation and where there is a scarcity of the dopamine transporter The NE transporter protein is a pivotal player in the regulation of catecholamines, involved in the re-uptake of both NE and DA into presynaptic terminals. Thus, it plays a key role in controlling the intensity and duration of signal transduction. The NE transporter is a member of the sodium- and chloride-dependent neurotransmitter transporter family, a transmembrane glycoprotein. SLC6A2 and ADHD. While initial studies were conducted with a limited number of single nucleotide polymorphisms (SNPs) SLC6A2 and ADHD endophenotypes, including neurocognitive measures Several family-based Although many studies have been conducted thus far, findings have been limited and difficult to replicate. An earlier study reported an association between rs3785157 and rs998424 and ADHD. SLC6A2 SNPs and response to MPH Although several pharmacogenetic studies, including a genome-wide association study, SLC6A2 and ADHD. In addition to the DSM-IV diagnosis of ADHD, quantitative behavioral and cognitive phenotypes, as well as response of these measures with MPH treatment, were tested for association. The panel of SNPs included those analyzed in the IMAGE project , We have conducted a family-based study to test the association between a panel of 30 SNPs within SLC6A2 after MSDP stratification.Given that high comorbidity between ADHD and cigarette smoking (35%–45%) is well documented The study was approved by the Douglas Mental Health University Institute (DMHUI) Research and Ethics Board. All participating children agreed to take part in the study, and parents provided written consent.Four hundred and seventy-five children with ADHD between 6 and 12 years of age  were included in this study. They were referred by schools, social workers, family doctors and pediatricians, and were recruited from the Disruptive Behavior Disorders Program and the children’s outpatient clinics of the DMHUI, a psychiatric teaching hospital in Montreal, Canada.Each child was diagnosed with ADHD according to DSM-IV criteria. Further details pertaining to diagnostic procedures have previously been described. T scores with an average of 50; where a score higher than 65 is considered to be clinical. The mean (standard deviation) for the total CBCL, Conners’-P, and Conners’-T scores were: 68.6 (8.9), 73.1 (11.4), and 69.5 (12.7), respectively, in this sample of children. Since it has been shown that a low to moderate correlation exists between parent and teacher reports of ADHD symptoms, and that each may assess a different dimension of the child’s behavior The Conners’ Global Index for Parents (Conners’-P) and for Teachers (Conners’-T) In addition to clinical dimensions of ADHD, neuropsychological measures, mainly of executive function (EF), were included as quantitative traits in the genetic association analyses. EF encapsulates the range of cognitive abilities that are important for self-regulation and goal-directed behaviors, including response inhibition, sustained attention, working memory, set-shifting, planning, and organization. Deficits in EF have been implicated in the underlying pathophysiology of ADHD. Response to treatment with methylphenidate (MPH) was assessed in a double-blind, placebo-controlled, within-subject (crossover) randomized control trial conducted over a two-week period, as described . off-task (looking away from the task sheet), playing with objects (touching any object not directly used in the task), out of seat (lifting buttocks off chair or moving chair), vocalizing , and fidgeting . The RASS score is the total number of recorded behavioral events, and the difference score is obtained by subtracting the score after MPH administration from the score obtained after PBO. We have previously reported results from principal component analysis of the RASS The Restricted Academic Situation Scale (RASS) was used to assess task-oriented behavior. During a simulated independent academic situation within a clinic setting Families were invited to participate in the genetic component of the study, where DNA was extracted, for each parent and child, from a blood sample, buccal swab, or saliva sample, if the subject was only amenable to the latter. Of the 377 nuclear families with one or more children diagnosed with ADHD, 184 were complete trios with information from both parents, 11 were trios with two affected children, 67 were trios with information from one parent and one or more unaffected sibling, 103 were duos including the proband and one parent, while 12 were families with two affected siblings and one parent.SLC6A2, previously examined in the IMAGE project, were genotyped SLC6A2, was also included in the panel, since it has been associated with ADHD SLC6A2, two SNPs  not genotyped in the IMAGE study, were also included in this study.Tag SNPs within SLC6A2.Sequenom iPlex Gold Technology Family-based tests of association  were conducted using the FBAT statistical package (version 2.0.3). Z = 2.54, P = 0.01), a highly significant association was observed on every measure tested, as well as treatment response in the stratified sample. The T allele of this SNP appears to be the risk allele for ADHD, showing an association with the categorical DSM-IV diagnosis . In the quantitative FBAT analysis, the T allele was over-transmitted to the higher number of inattention , hyperactivity , and impulsivity  items on the DISC-IV, higher CBCL total scores  , higher restless-impulsive subscale scores of Conners’-T  and Conners’-P . Taken together, this suggests that the T allele is associated with more severe psychopathology, as assessed in the home, school, and clinic.As noted in Z = 3.69, P = 0.0002), CPT and WCST . The risk allele was over-transmitted to the higher scores, with higher T-scores implying worse performance. In particular, an association was noted with several dimensions evaluated in this test – hit reaction time (RT) standard error (SE)  and variability of SE . High T-scores on these measures indicate highly variable reactions to the “target” and “non-target”, often related to inattentiveness. Z = 3.74, P = 0.0002) and hit SE block change . Here, the higher T-scores indicate a slowing in reaction time, as well as a loss of consistency, which together suggest a loss of vigilance, as the test progresses. The risk allele was also associated with poor performance on the WCST, which measures cognitive flexibility and set-shifting. The T allele showed an under-transmission (negative Z score) to the higher scores, specifically with non-perseverative errors (the higher standard scores imply a better performance on the test) . No association was observed with perseverative errors or responses. On the WCST, perseverative errors occur due to an inability to shift set, despite negative feedback. T allele at rs36021 exhibit EF deficits, specifically sustained attention (characterized by distractibility during the task and loss of vigilance as the test progresses), spatial working memory, planning, and response inhibition.In terms of cognitive function, the risk allele was associated with worse performance on the SOPT , Conners’-P , as well as evaluation in the simulated academic environment, . Based on the factor structure of the RASS, Z = 3.44, P = 0.0006), but not with the other factors.The reatment . The risSLC6A2 and one or more behavioral/cognitive measures. These included: rs41154, rs187714, and to a lesser extent, rs4783899, rs2397771, and rs192303. Based on calculation of D’ and r2 in Haploview, it was noted that these markers are in strong LD with rs36021 , RASS task-disengagement (PBO – MPH) . No association was observed with rs36021 in this group. It is interesting that two adjacent SNPs (rs36021 and rs3785152) show highly divergent association in the two groups. In fact, LD between these two SNPs is low  is observed.The association between MSDP and ADHD is one of the most investigated in the field of environmental psychiatric epidemiology. Although consistently replicated in utero exposure to the toxic effects of nicotine are well documented, from animal and human studies. SLC6A2 to increase the risk for ADHD in children. Under the latter scenario, MSDP may be considered as a phenotypic index used to select a subgroup of children with relatively more homogeneous genetic etiology.Given that the association between ADHD and rs36021 (and linked SNPs) is highly significant only in those children whose mothers smoked during pregnancy may suggest a true interaction between exposure to maternal smoking and carrying the risk allele(s) in the SLC6A2 gene. Indeed, the adverse consequences of SLC6A2 is an important factor in a more severe subtype of ADHD. If replicated in independent studies, this may represent an important step towards personalized medicine in treating children with ADHD. Irrespective of the precise links between these pathways, this study strongly suggests that genetic variation in the et alet al, G allele to the higher difference scores was observed in the quantitative FBAT analysis on the Conners’-T  are within introns, opening up two possibilities. The first possibility is that these intronic variants are involved in gene regulation. The second is that these polymorphisms are not the causal mutation, but are in LD with a functional variant. Fine-mapping of the region is required to identify the causal mutation(s) followed by molecular analysis to determine if the mutation affects transcriptional regulation of the gene or structure and function of the protein.SLC6A2 and ADHD in children stratified according to MSDP, the primary result of association  with rs36021 remains significant even if we apply the overly stringent Bonferroni correction . In addition, the widespread exploratory associations that are observed with behaviors relevant to ADHD measured by different observers  and in different settings  with rs36021 suggest that these associations are unlikely to be chance findings. We believe that this considerable consistency of results strengthens the overall credibility of the primary results and help to understand how genetic vulnerability to ADHD is mediated through the traits and endophenotypes underlying this disorder.While we conducted a large number of comparisons and some correction for multiple testing is warranted, it is important to note that when we correct for multiple testing in relation to our primary hypothesis, that is association between SLC6A2, with such detailed genotype and phenotype characterization. While collaboration between multiple research groups in large consortia is vital for genetic studies of ADHD, it has been shown that a significant amount of heterogeneity can be introduced in multicenter collaborative studies because of divergent clinical and evaluation practices. To our knowledge, this is the largest study (among family-based and case-control studies) testing the association between ADHD and If confirmed in independent studies, these results will help to disentangle the complex etiological pathways of ADHD. In the long term, this would very likely lead to development of therapeutics targeting specific biochemical pathways in specific sub-groups of children with ADHD.


Background: Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed childhood psychiatric disorder. Disrupted sustained attention is one of the most significant behavioral impairments in this disorder. We mapped systems-level topological properties of the neural network responsible for sustained attention during a visual sustained task, on the premise that strong associations between anomalies in network features and clinical measures of ADHD would emerge.Methods: Graph theoretic techniques (GTT) and bivariate network-based statistics (NBS) were applied to fMRI data from 22 children with ADHD combined-type and 22 age-matched neurotypicals, to evaluate the topological and nodal-pairing features in the functional brain networks. Correlation testing for relationships between network properties and clinical measures were then performed.Results: The visual attention network showed significantly reduced local-efficiency and nodal-efficiency in frontal and occipital regions in ADHD. Measures of degree and between-centrality pointed to hyper-functioning in anterior cingulate cortex and hypo-functioning in orbito-frontal, middle-occipital, superior-temporal, supra-central, and supra-marginal gyri in ADHD. NBS demonstrated significantly reduced pair-wise connectivity in an inner-network, encompassing right parietal and temporal lobes and left occipital lobe, in the ADHD group.Conclusions: These data suggest that atypical topological features of the visual attention network contribute to classic ADHD symptomatology, and may underlie the inattentiveness and hyperactivity/impulsivity that are characteristics of this syndrome. Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric condition of childhood , state factors , and an overriding management or executive system associated with planning, monitoring, detection of errors, and error correction and network-based statistics (NBS) has provided powerful approaches to characterization of the topological properties of functional brain networks from neurophysiological datasets  of children and adults with ADHD , have been widely employed in the diagnosis of ADHD Conners, . During SD) on all Conners subscales. For both groups, we included the K-SADS-PL screening questions and supplements to rule out pervasive developmental disorders, substance use and abuse, and posttraumatic stress disorder. Similarly, oppositional defiant disorder with physical aggression (using DSM-IV diagnostic criteria), and all other current Axis I disorders (except for fear of the dark) were exclusionary. Children with any specific learning disorders were also excluded. The basic reading, mathematical reasoning, reading comprehension, and numerical operations subtests of the Wechsler Individual Achievement Test 2nd ed (WIAT-II) . This attrition left a total of 22 children with ADHD combined-type and 22 typically developing children (TDC) for inclusion in the main analyses. Diagnostic assessment of ADHD was performed using the revised long versions of Conners' Parent/Teacher Rating Scales (CPRS/CTRS) for both parent and teachers reports Conners, . The CPRAll subjects had normal or corrected-to-normal vision. Nine children in the ADHD group had been treated with short-effect stimulant medication . A 48 h wash-out period was undertaken by the care-givers of each of these patients before the day of MRI scanning to mitigate against potential medication effects on brain activations during fMRI task performance.The children with combined-type ADHD were recruited from the Children's Evaluation and Rehabilitation Center at The Albert Einstein College of Medicine, and the Parnes Clinic at the Ferkauf Graduate School of Psychology. The TDC were recruited from local schools through newspaper advertisements, in collaboration with the Human Clinical Phenotyping Core of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK-IDDRC) at The Albert Einstein College of Medicine. This study received IRB approval for human subjects' research at Albert Einstein College of Medicine and all procedures consistent with the ethical standards laid out in the Declaration of Helsinki. After the study procedures were carefully explained, written informed consent was provided by all participants and their parents.We employed a block-design CPT that consisted of 5 task blocks interleaved with 5 rest blocks. Each block lasted for 30 s. In each task block, a target sequence of 3 digits in red typeface  was first shown in the center of the LCD screen, at the rate of one digit each 400 ms. Then, following a 1.8 s delay during which participants were required to remember the potential target sequence, a series of 9 additional 3-digitprobe sequences were presented sequentially in black typeface in a pseudo-random order, again at a rate of one digit every 400 ms. A 1.8 s response window followed each 3-digit probe sequence. In this period, participants were instructed to press the left button of a response pad using their index finger if the probe sequence matched the originally presented target sequence, and to use the middle finger to press the right button otherwise. During the rest blocks, a red cross was shown in the center of the LCD panel and participants were instructed to keep their eyes open, to maintain fixation, and to remain as relaxed and motionless as possible. The duration of the entire task was 5 min. Further details of design and rationale for the use of this CPT have been previously described  with 240 × 240 in-plane matrix and 1 mm partition thickness (1 mm isotropic resolution), TE = 4.6 ms, TR = 9.8 ms, α = 8o, SENSE factor = 2).Imaging data were obtained using a 3.0 Tesla 32-Channel FreewaveAchieva MRI Scanner . fMRI data acquisition utilized whole brain gradient echo-planar imaging (EPI) sequence over a 230 ×128 acquisition matrix with 2 mm slice thickness, and 2 × 2 mmThe fMRI data from each participant were pre-processed using the FSL/FEAT tools regions of interest (ROIs) were chosen based on our previous findings which identified them as key nodes in the normal visual attention processing pathway  and a cluster-corrected significance threshold of p < 0.05.Finally, a high-pass temporal filter of 1/80 Hz was used to remove low-frequency noise. Non-brain structures were removed. The fMRI data were first aligned to the skull-stripedT1-weighted image from the same participant using an affine translation, and further registered to the MNI152 template using linear registration. Nine components including the six motion correlation parameters and nuisance signals  in the time series were regressed out from each fMRI dataset. The task-responsive activation maps in each individual and the average maps for each group were then generated by using the FSL/FEAT tool. The Z statistic image was thresholded using clusters determined by A total of 68 spherical seed ROIs (radius = 5 mm) were identified from a combination (union) of the brain clusters that were significantly activated in the average activation maps in the ADHD or TDC groups. This combined activation map was parcellated according to the automated anatomical labeling (AAL) template , G, was defined as following:N and K are the total number of nodes (ROIs) and edges , respectively; N(N-1)/2 was the number of all the possible edges in the graph G  and local efficiency, locE(G), defined as:ijl is the shortest path length between nodes i and j; globE(G) the global efficiency of the sub-network iG that is constructed by the set of nodes that are immediate neighbors of nodes i  < globE(G) < globE(randomG) and locE(randomG) < locE(G) < locE(regularG), where globE(regularG), globE(randomG), locE(regularG), and locE(randomG) were the global and local efficiencies of node-and degree-matched regular and random networks.The functional connectivity matrix was converted into a binary graph, by using the network cost as threshold. The cost G  or betweenness-centrality (BC), of this node was significantly higher than the average value over all the nodes in the network. The degree (iD) of a node i was the number of edges connected to the node i. The betweenness-centrality (iBC) of node i was defined as the proportion of all the shortest paths between pairs of other nodes in the network that include node i  was calculated at each cost value, from cost = 0.05 to 0.3, by using increments of 0.01. The mean value was then calculated for following statistical analysis . We selected the mean of the measure between cost = 0.05 and 0.3, because this was the small-world regime identified in both groups. These standardized z-values were then tested with a normal distribution. A node i was defined as a network hub if the one side p-value in the z-test, p = 1 − Φ(iz), is less than 0.05 , where Φ(·) was the standard normal cumulative distribution function.The network hubs were also identified in each group. In this study, a node was defined as a hub if the value of a measure, either degree (http://www.nitrc.org/projects/nbs/), was applied to perform this part of analysis. The NBS seeks to identify any potentially connected regions formed by an appropriately chosen set of suprathreshold links. The topological extent of any such region is then used to determine its significance. It was performed as follows: (1) For each participant, the raw measurement-based functional connectivity matrix, constructed based on the (68 × 67)/2 = 2278 pairs of ROIs, was calculated. (2) A between-group t-test of the absolute Pearson correlation coefficient of each pair of the regions was calculated. This step was repeated independently in the 2278 pairs of ROIs. (3) Pairs of regions, which had a t statistic exceeding a threshold 3.5 , and there were no significant correlations between Mean Motion and the functional connectivities in the thalamo-prefrontal and thalamo-occipital pairings across the whole sample . Stastical analysis indicated that there were no significant differences in the fitted parameters (α: t(36) = 1.306, p = 0.9; kc: t(36) = 0.659, p = 0.864 between two groups.Figures F = 6.67, df = 1, 35, p = 0.014) and right superior occipital gyrus , but had significantly increased nodal efficiency in the left cuneus , after controlling for possible age, IQ and gender effects.Group comparisons of the nodal efficiencies of all the nodes over the small-world regime showed that patients had significantly reduced nodal efficiencies in the left superior orbito-frontal gyrus , and significant positive correlation between nodal efficiency in the ACC and inattentiveness scores. The ACC has been implicated as a major coordinating hub within multiple cognitive control networks  relative to an even larger control dataset (N = 455) , and significantly decreased nodal efficiency in the medial prefrontal, temporal, and occipital regions in children with ADHD (Wang et al., There are limitations to this study that need to be acknowledged. First, sex-related heterogeneity is likely to exist in ADHD (Rubia et al., As outlined in the methods section, controlling for head motion is a crucial issue in studies of functional connectivity, where relatively modest levels of motion can result in substantial image distortion and induce BOLD signal noise in both resting-state and task-based fMRI data. Further, more severe image distortion and signal noise will occur in voxels at the extremities of the brain volume when rotation along a perpendicular direction is incorporated. This likely explains prior results showing that long-range connections are more vulnerable in such calculations (Power et al., Dr. Ariane Sroubek contributed to subject recruitment, clinical assessment, and MRI data management. Drs. Shugao Xia and Xiaobo Li contributed to data analyses and results generation. Drs. Shugao Xia, John J. Foxe, Craig Branch, and Xiaobo Li contributed to manuscript writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The effects of prenatal Zinc Deficiency (ZD) and Vitamin A Deficiency (VAD) on birthweight are controversial and their interaction has not been investigated.To assess the independent and interaction effects of prenatal zinc and vitamin A deficiencies on birthweight in rural Sidama, Southern Ethiopia.A community-based prospective cohort study design was employed. Six hundred fifty pregnant women in their second or third trimester were randomly selected and their serum zinc and retinol concentrations were determined. About 575 subjects were successfully followed until delivery and birthweight was measured within 72 hours after delivery. The association between the exposures and birthweight was examined using log-binomial and liner regression analyses. Potential interaction between ZD and VAD was examined using Synergy Index (SI).The mean birthweight (± standard deviation) was 2896 g (±423). About 16.5% (95% CI: 13.5–19.6%) of the babies had Low Birthweight (LBW). Prenatal ZD and VAD were not significantly associated to LBW with Adjusted Relative Risk (ARR) of 1.25 (95 CI: 0.86–1.82) and 1.27 (95% CI: 0.86–1.87), respectively. Stratified analysis on the basis of gestational trimester showed that the occurrence of the deficiencies neither in the second nor third trimester were associated to LBW. The deficiencies did not show synergetic interaction in causing LBW [SI = 1.04 (95% CI: 0.17–6.28)]. Important risk factors of LBW were maternal illiteracy [RR = 1.80 (95% CI: 1.11–2.93)], female sex of the newborn [RR = 1.79 (95% CI: 1.19–2.67)], primiparity [RR = 1.16 (95% CI: 1.02–1.35)], short maternal stature [RR = 1.63 (95% CI: 1.06–2.51)] and maternal thinness [RR = 1.52 (95% CI: 1.03–2.25)]. In the linear regression model, elevated CRP was also negatively associated to birthweight.LBW is of public health significance in the locality. The study did not witness any independent or interaction effect of prenatal ZD and VAD on birthweight. Low birthweight (LBW) is the single most important predictor neonatal survival and a significant determinant of post-neonatal infant mortality, childhood morbidity and cognitive development In Ethiopia a handful of studies attempted to determine the prevalence of LBW. A community-based study in Southwestern Ethiopia found 10% prevalence Studies endeavored to evaluate the effect of prenatal zinc supplementation on birthweight concluded equivocally. A recent meta-analysis of Randomized Control Trials (RCTs) concluded that taking zinc during pregnancy does not prevent LBW but slightly reduces preterm birth Pertaining vitamin A, a meta-analysis concluded that prenatal vitamin A supplementation does not significantly reduce risk of LBW The purpose of the current study is to investigate the independent and interaction effects of prenatal zinc and vitamin A deficiencies on birthweight in rural Sidama, Southern Ethiopia. The study also assessed the prevalence and general determinants LBW. Despite the existence of many RCTs and observational studies which evaluated the effect of prenatal zinc and vitamin A status on birthweight, the current study is worth documentable as it has been conducted in area with high prevalence of zinc and vitamin A deficiencies. Further the potential interaction effect of the two deficiencies on birthweight had not been studied before.The study was conducted based on cohort data of 575 pregnant women in the aforementioned locality. Earlier, another article This is a community-based prospective cohort study. Pregnant women were classified based on their prenatal serum zinc and vitamin A statuses and followed until birth. Birthweight was measured within 72 hours of birth.The study was conducted from January to October 2011 in 18 randomly selected rural kebeles of Sidama zone, Southern Ethiopia. A kebele is the smallest administrative unit in Ethiopia comprising roughly 1000 households. In Sidama zone, of the total population nearing three million, 95% dwells in rural areas. The livelihood of 85% of the population depends on subsistent farming. Nearly half of the population lives in the midlands (1750 to 2300 m above sea level (ASL)); whereas 30% and 20% dwell in the highlands (>2300 m ASL) and lowlands (<1750 m ASL), respectively. On average a household in Sidama has 4.9 dwellers, 0.3 hectares of land and 0.5 heads of livestock. The detail description of the study area has been given elsewhere Pregnant women whose zinc and vitamin A statuses were determined at their second or third trimester and who later gave singleton live-births were eligible for the study. Babies visited after 72 hours of birth were excluded. Women whose exposure was determined in the first trimester were also excluded as the fetal weight gain in first trimester is known to be minimal. Flowchart of the cohort from exposure assessment to outcome ascertainment is given as follows .The baseline study was designed to enroll 750 pregnant women. The basis of the sample size calculation has been given elsewhere As described elsewhere As described in the previous paper The occurrence of births in the cohort were promptly identified and reported by prearranged local community health promoters and birthweight was measured within 72 hours of birth by trained health extension workers. Weight was measured to the nearest 100 g using calibrated Docbel BRAUN® scale.Blood samples were collected, stored, transported and processed following standard procedures. Six ml of blood was collected from antecubital vein using plain and closed SARSTEDT® blood collection system and stainless steel needles. The blood was allowed to clot for 20 minutes and centrifuged at 3000 rotations per minute for 10 minutes. Serum was extracted into screw-top vials within 40 minutes of sample collection. During this time few obviously hemolyzed samples were identified and discarded. In the entire process, the samples were protected from dust and direct light. In the field the samples were kept in icebox. The same day they were transported in icebox and kept frozen at −20°C until analyzed.Serum zinc and retinol concentrations were determined at Ethiopian Health and Nutrition Research Institute using Varian SpectrAA® Flame Atomic Absorption Spectrometer and Shimadzu® High Performance Liquid Chromatography, respectively. C-Reactive Protein level (CRP) was determined qualitatively using latex HumaTex® kit.Data entered, screened and principally analyzed using SPSS 19.0. Additional analysis was made via STATA/SE 11.0. Independent t-test and one-way Analysis of Variance (ANOVA) were used to compare birthweight across categories of independent variables. Two of the major assumptions of ANOVA  were checked to be satisfied.Wealth index was computed using Principal Component Analysis (PCA) as a composite indicator of living standard. A total of 23 variables related to ownership of selected household assets, size of agricultural land, quantity of livestock, materials used for housing construction, and ownership of improved water and sanitation facilities were considered for the analysis. Ultimately, seven principal components having eigenvalues greater than one were identified. Wealth index value was calculated by summing up the scores for the seven principal components. Ultimately, the five categories  were generated by splitting the wealth index values into 5 equal classes.Log-binomial regression was used to control confounders and to model the risk LBW as function of multiple factors. In accordance with the framework of Kramer Linear regression analysis was also used to control confounders and to assess the association between birthweight and various covariates. However, in this case only the direct factors were modeled as the r-squared value for indirect factors was found to be low. As the case of the log-binomial model, independent variables that turned out to be significant in bivariate linear models were considered for multivariate analysis. The major assumptions of the analysis  were not violated. The fitness of the multivariate model was assessed using the adjusted r-squared value.Potential interaction between ZD and VAD in causing LBW was measured on additive scale. The additive scale is preferred as it is known to be correlated with biological interaction The study was conducted in confirmation of national and international ethical guidelines for biomedical research involving human subjects. Ethical clearance was secured from the institutional review board of Addis Ababa University. Informed written consent was taken from the study subjects. Nutrition education was given to all subjects and anemic women were given iron-folate supplementation.(P>0.05)  were included in the ultimate analysis. The exclusion was on the bases of loss to follow-up (34), birthweight measurement taken after 72 hours of birth (22), fetal loss (9), multiple birth (6) and early neonatal death (4). The retained and excluded subjects were not statistically different in terms of wealth index, agro-ecological zone, literacy, CRP status, maternal height, maternal MUAC, prenatal serum zinc and retinol concentrations (P>0.05) .During the baseline survey 304 (52.9%) and 271 (47.1%) of the women were in their second and third gestational trimesters. Their mean age (± standard deviation) was 28.5 years (±5.4). Nearly half, 299 (52.0%), were from the midlands and the remaining 154 (26.8%) and 122 (21.2%) were from the highlands and lowlands, respectively. About two-third, 381 (66.3%), were illiterates and four-fifth, 462 (80.3%), were housewives. Among babies weighed, 289 (50.3%) were males.The mean birthweight (± standard deviation) was 2896 g (±423). About 16.5% (95% CI: 13.5–19.6%) of the babies were born with LBW.. The risk of LBW was 1.80 (95% CI: 1.11–2.93) times higher in the earlier group. The mean birthweight increased from 2829 g in the poorest to 2951 g in the richest wealth quintiles. Yet the difference was not significant . The prevalence of LBW in the five wealth quintiles were; poorest (23.2%), poorer (19.0%), middle (16.0%), richer (12.6%) and richest (12.3%). However in the log-binomial model the difference was not statistically significant. Likewise women involvement in Income Generating Activities (IGA) was not associated to LBW  was significantly higher than illiterates (2831 g±405) d to LBW . and females were 1.79 (95% CI: 1.19–2.67) times prone to LBW. The weight of babies born to primiparous women (2744 g±432) was significantly inferior to those born to parous women (2924 g±415) . The risk was 1.16 (95% CI: 1.02–1.35) times elevated in the earlier group  er group .. Yet in the multivariate log-binomial model the association was not significant (RR = 1.26 (95% CI: 0.76–2.09)) (The weight of babies born to women who had elevated CRP during pregnancy (2748 g±429) was significantly lower than their counterparts (2910 g±429) 6–2.09)) .. Likewise a 195 g (95% CI: 95–294 gm) significant difference was observed between babies born to non-stunted and stunted women. The risk of LBW was 1.63 (95% CI: 1.06–2.51) and 1.52 (95% CI: 1.03–2.25) times elevated in stunted and thin women, respectively . Hence, they were not considered for the multivariate analysis. Sex of the newborn, primiparity, maternal age, serum retinol, serum zinc, maternal height, MUAC and CRP status were exported to the multivariate model as they were significant in the bivariate analysis. In the ultimate model sex, primiparity, height, MUAC and CRP status were significant predictors of birthweight.In the bivariate linear regression model altitude of the kebeles, number of ANC visits, diastolic blood pressure during pregnancy were not associated to birthweight The final model explained 20.9% of the variability in birthweight . A cm inLBW is considered as a problem great enough to trigger public health action when its incidence exceeds 15% Due to the community-based nature of the study it was only possible to weigh newborns within 72 hours of birth. As birthweight is known to decline by 5–7% in the first three days of life In Ethiopia very few studies attempted to determine the prevalence of LBW. Most were conducted in major referral hospitals. The reported prevalence figures ranged from 8.6 to 15.4% The study did not witness significant association between prenatal zinc status and infants' birthweight. The finding is in confirmation of the conclusion a meta-analysis that maternal zinc supplementation does not enhance birthweight Observational studies on the relationship between maternal vitamin A and birthweight in apparently health subjects concluded divergently. A study in Israel reported that cord retinol along with gestational age explained more than a quarter of the variability of birthweight In the current study the concurrent presence of VAD and ZD during pregnancy showed marginally insignificant effect on LBW (95% CI of 1.00–3.11). Nevertheless, it is important to interpret the finding in consideration of the fact that the sample size of the study was only calculated for the evaluation of the independent effect of the deficiencies on birthweight. Hence, in the measurement of the joint effects of the deficiencies on birthweight, the power of the study might have been compromised. Accordingly, in this area, further studies with optimal sample size are evidently required.The fact that maternal zinc and retinol concentrations were measured only once during the entire pregnancy can potentially over or under estimate their association with birthweight as the exposure status to the deficiencies might not be fixed. Nevertheless, among women who were at their second gestational trimester during the baseline survey, follow-up survey conducted during their third trimester showed no significant change in their dietary diversity, food frequency and consumption of animal source foods. This might be taken as supporting evidence that their exposure status had not been assorted remarkably.The linear regression model explained merely 20% of the variability in birthweight. This might have happened as some of the key predictors of low birthweight like weight gain during pregnancy, pre-pregnancy weight and malaria during pregnancy were missed from the model. A study showed that in the developing world the aforementioned factors can roughly explain 40% of the variability of birthweight Further, both in the linear and log binomial models, gestational duration has not been included as a covariate despite the fact that it is an important predictor of birthweight. This was due to the obvious difficulty of measuring gestational age in rural areas of developing countries where access to ultrasound is limited and estimation based the date of last menstrual period lacks accuracy. The exclusion of the variable from the regression analyses might have compromised the comprehensiveness of the models.Several studies witnessed the positive contribution of superior household wealth status in reducing the burden of LBW In the current study male babies weigh more than females by about 100 gm and the risk of LBW was 1.8 times raised in females. Previous studies in Ethiopia and abroad concluded likewise Both in the log-binomial and linear regression models maternal MUAC was a strong correlate of birthweight. Especially in the linear model, removing the variable from the equation reduces the r-squared value from 21% to 12%. Even the study might have underestimated the association as pregnant women are commonly enrolled into supplementary and therapeutic feeding programs based on their MUAC. Studies in India Maternal height was also a strong predictor of birthweight. This is consistent to the understanding that in the developing world approximately 12% of low birthweight can be explained by maternal short stature Unlike several studies that witnessed the beneficial effect of ANC in reducing the burden of LBW In the linear regression model elevated CRP during pregnancy was an important predictor of birthweight. The finding is in confirmation of the result of a systematic review that in the developing world approximately 4% of the burden of LBW is attributed to general illnesses during pregnancy and an extra 10% can be linked to malaria The prevalence of low birthweight was 16.5%. LBW is of public health significance in the locality. Prenatal vitamin A and zinc deficiencies occurring in the second or third trimesters were not associated with increased risk of LBW. Similarly, the two deficiencies did not show synergetic interaction in causing LBW. Important risk factors of LBW were maternal thinness and stunting, primiparity, female sex of newborn and elevated CRP.


The structure of whole grain cereals is maintained to varying degrees during processing and preparation of foods. Food structure can influence metabolism, including perceived hunger and satiety. A diet that enhances satiety per calorie may help to prevent excessive calorie intake. The objective of this work was to compare subjective appetite ratings after consumption of intact and milled rye kernels.Two studies were performed using a randomized, cross-over design. Ratings for appetite  were registered during an 8-h period after consumption of whole and milled rye kernels prepared as breads  and porridges . Sifted wheat bread was used as reference in both study parts and the products were eaten in iso-caloric portions with standardized additional breakfast foods. Breads and porridges were analyzed to determine whether structure (whole vs. milled kernels) effected dietary fibre content and composition after preparation of the products. Statistical evaluation of the appetite ratings after intake of the different breakfasts was done by paired t-tests for morning and afternoon ratings separately, with subjects as random effect and type of breakfast and time points as fixed effects.All rye breakfasts resulted in higher satiety ratings in the morning and afternoon compared with the iso-caloric reference breakfast with sifted wheat bread. Rye bread with milled or whole kernels affected appetite equally, so no effect of structure was observed. In contrast, after consumption of the rye kernel breakfast, satiety was increased and hunger suppressed in the afternoon compared with the milled rye kernel porridge breakfast. This effect could be related to structural differences alone, because the products were equal in nutritional content including dietary fibre content and composition.The study demonstrates that small changes in diet composition such as cereal grain structure have the potential to effect feelings of hunger and satiety.NCT01042418.This trial was registered at clinicaltrials.gov as  A high intake of dietary fibre and whole grain foods is associated with a lowered risk of body weight gain, partly owing to an increased feeling of satiety preventing excess energy intake ,2. SatieA few studies have investigated the impact of cereal grain structure on satiety. Two studies on whole grain wheat showed that breads including whole kernels increased satiety more than breads made with whole grain flour, at 15 min after intake  and duriThe aim of the present study was to investigate if variation in rye grain structure influences perceived appetite during 8 hours. Whole rye kernels and milled rye kernels were compared in a two-part study. The first part compared breads made with milled and whole rye kernels, and the second part porridges of milled and whole rye kernels. Both study parts included a reference breakfast with sifted wheat bread. Special efforts were taken to analyze potential differences in dietary fibre content and composition between the products made from whole or milled rye kernels.2; habit of consuming breakfast, lunch and dinner every day; and willingness to comply with the study procedures. Exclusion criteria were the following: intake of medicine likely to affect appetite or food intake; any medical condition involving the gastrointestinal tract; eating disorder; smoking; consumption of more than three cups of coffee per day; change in body weight more than 10% during three months prior to screening; consumption of any restricted diet such as vegan, gluten-free, slimming, etc.; pregnancy, lactation or wish to become pregnant during the study period.Subjects were recruited by sending an inquiry via e-mail to students and employees at the Swedish University of Agricultural Sciences, Uppsala, Sweden. Volunteers were further informed in person about the study procedures and screened to determine their eligibility for inclusion. The criteria for inclusion were the following: man or woman aged between 20 and 60 years; body mass index (BMI) 18-27 kg/mWeight and height were measured with the subjects wearing light indoor clothing but no shoes and the data obtained were used to calculate BMI. Capillary blood samples were taken in the fasting state for analysis of glucose, thyroid-stimulating hormone, and haemoglobin and alanine aminotransferase.Initial recruitment started in October 2008 for the bread study, which was performed over 5 weeks starting in early November 2008. All subjects participating in the bread study were invited to the porridge study, which was performed over 5 weeks starting in early April 2009. Written informed consent was obtained from each subject. The study was carried out in compliance with the Helsinki Declaration and was approved by the Ethics Committee at Uppsala University, Sweden.A randomized, cross-over design was used, with three treatments in each of the two study parts. The test sessions (08:00-16:00) were separated by between 5 and 15 days during which the subjects were asked to follow their ordinary diet. The subjects were not informed about the aim of the study or about the content of the test products. On the day prior to each test day, subjects were instructed not to conduct any vigorous physical activity or drink any alcoholic beverages. They were also instructed to eat dinner before 20:00 and to keep the dinner meal similar before each test occasion. They were instructed not to eat or drink anything but water after 20:00.Upon arrival in the morning (08:00) on test days, each subject was served one of the test breakfasts. During eating, they were seated in a dining area and allowed to make conversation but not regarding anything relating to the study. The subjects were seated at separate tables according to which breakfast they were served, so that those sitting together were eating the same type of breakfast. At the beginning of each session, subjects were asked to fill out questionnaires regarding food and beverage consumption and exercise pattern from the previous evening. After finishing the breakfast meal, the subjects received a lunch bag to be eaten at 12:00 and were free to return to their normal daily activities, such as office work or studies. During the day, they were not allowed to conduct any heavy physical activity, including brisk walking, and restricted to stay within the campus area. They were not allowed to eat or drink anything except foods included in the study diet and moderate amounts of water. A compliance form was filled out by each subject during the day to ensure that instructions were followed.Subjective feelings of appetite were assessed every 30 min, starting just before breakfast at 08:00 and continuing until 16:00. The data were collected using a specially designed program  on a hanAt 16:00, the subjects returned to the dining area to hand in the palm computers and compliance forms. They were asked about any complications during the day. In the porridge study, the subjects wore pedometers to count steps taken between 08:00 and 16:00.For the bread study, rye kernels commercially used in breads were used . These untreated kernels were slightly cracked by rolling (2 mm) in order to decrease the time for water absorption and soften the consistency. Rye kernels developed for use as a rice replacer  were used in the porridge study. These kernels were steamed before being lightly cracked by rolling (1.8 mm) in order to decrease cooking time. Both types of rye kernels described above were used whole and milled to fine whole grain flours using a laboratory mill . Commercial sifted wheat flour of high quality  was used in all breads, including the wheat reference bread.Three types of bread were made in a small-scale bakery; bread with whole rye kernels, bread with milled rye kernels and wheat reference bread. To create breads with acceptable palatability and soft texture, rye comprised 50% of the total amount of flour. A higher content of rye resulted in compact, crumbly breads, with low ability to prove during fermentation.Soaked rye kernels were prepared by adding rye kernels (900 g) to a pot of boiling water (1350 g) and left to soak under lid for 60 min. Soaked milled rye kernels were prepared by adding boiling water (1350 g) to milled rye kernels (900 g) in a plastic container. After mixing by hand, the blend was covered with plastic wrapping and left to soak for 60 min.Both of the rye breads were then baked according to the same procedure. The soaked rye was mixed with sifted wheat flour (900 g), fresh baker's yeast (75 g), gluten (150 g), rape seed oil (90 g), syrup (90 g) and salt (27 g) and kneaded for 7 min using a mixer . The dough was left to rest at room temperature (~22°C) for 10 min, then weighed and divided equally into six loaves. The loaves were left to prove for 30 min at 34°C and then baked at 200°C for 40 min.The wheat reference bread was made by mixing sifted wheat flour (1800 g), water , fresh baker's yeast (75 g), gluten (150 g), rapeseed oil (90 g), syrup (90 g) and salt (27 g) for 7 min. The dough was left to rest at room temperature for 10 min and then weighed and divided equally into six loaves. The loaves were left to prove at 34°C for 30 min and then baked at 200°C for 30 min. The wheat bread used as reference in the porridge study was baked in the same way, except that gluten was excluded.After cooling for approximately 2 h, the ends of the loaves were removed. Test portions were weighed, packed individually into plastic bags and stored frozen until the night before each test breakfast.The porridge of whole rye kernels was prepared by adding rye kernels (66 g) and salt (0.75 g) to boiling water (155 g) and simmering gently for 11 min. By then all water was absorbed by the kernels.The porridge of milled rye kernels was made by adding milled rye (66 g) kernels to boiling water (350 g), removing the pot from the heat and whipping the contents for 4 min to a smooth porridge.Food intake was standardized in terms of type, amount and timing during the 8-h test period. The test breads were served with the following additional foods: 10 g margarine (40% fat), 24 g cheese (28% fat), 200 g orange juice and one cup of tea or coffee. In the porridge study, the following additional breakfast foods were used: 10 g margarine (40% fat), 60 g lingon berry jam and 200 g milk (1.5% fat). The subjects were allowed one cup of tea or coffee with up to two sachets of milk . Choice of hot drink was individually standardized between test occasions. No sugar or sweetener was allowed. The breakfast meals provided 2550 kJ in the bread study and 1850 kJ in the porridge study. The standardized lunch used in both study parts consisted of a ready-made vegetarian pasta dish of 400 g providing 2040 kJ, 21 g of protein, 64 g of carbohydrates and 16 g of fat per dish  and was served with 40 g of cherry tomatoes and 40 g of cucumber. The breakfast and lunch meals had to be consumed entirely and within 30 min. At 14:00, the subjects ate an apple and could choose to drink a cup of tea or coffee, the drink was then kept identical on the following test days.wM) and number-average (nM) molecular weights were determined using high performance size exclusion chromatography coupled with multiple angle laser light scattering and refractive index detector [cfM) was analyzed using size exclusion chromatography with fluorescence detection and Calcofluor concentration 0.0025% [4 g/mol are not detected and were thus excluded from the results. Fructan molecular weight distributions were determined by high performance anion exchange chromatography coupled with amperometric detection [Breads and porridges were freeze-dried, homogenized in a cyclone sample mill  and stored at -20°C. In order to obtain representative samples of the porridges, samples were collected every test week. All the samples were analyzed at least in duplicate and results are reported on a dry matter basis. Dry matter was determined by drying the samples at 105°C for 16 h according to the AACC method 44-15A . Fructan 0.0025% . MoleculRatings for satiety, hunger, and desire to eat were analyzed using Minitab . The level of significance was set at p < 0.05. Missing values (< 1%) were replaced by an average of the ratings for the same point in time and treatment. ANOVA was performed as paired t-tests and Tukey comparisons using subjects as random effect and type of breakfast and time points as fixed effects. Separate analyses were performed for morning (08:30-12:00) and afternoon ratings (12:30-16:00).Of the 27 subjects recruited initially, 24 complied with the study procedures and completed the bread study. The three drop-outs were caused by illness (not related to the study), energy requirements exceeding those given in the standardized study diet and not meeting the health criteria. In the porridge study, 20 subjects of the 23 recruited initially met the criteria and completed the study. The three drop-outs were caused by failure to comply with the study procedures. All subjects were within a healthy range of measured health parameters Table . ResultsWithin each study part, test products were served in portions providing similar caloric, protein, fat and available carbohydrate content Table , togetheThe breakfast and lunch meals were well liked and finished completely within 30 min. No adverse events were recorded. Anecdotally, many commented on the large portion size of the porridges, especially the milled kernel porridge.The total dietary fibre content including fructan in the breads with whole rye kernels (12%) and milled rye kernels 13%) differed only slightly  than in the bread made from whole rye kernels  was very similar in the two porridges Figure . The proTaken together, disintegration of the rye kernels had little impact on molecular weight parameters of extractable arabinoxylan, β-glucan and fructan in porridges made from whole kernels and milled rye kernels, while some differences could be seen between the two rye breads.Before breakfast, the mean ratings for hunger, satiety and desire to eat were similar between test days Figure . AppetitSatiety was rated higher during the morning 08:30-12:00) after intake of both rye bread breakfasts  increased satiety more than bread with whole grain wheat flour during 2 h after intake .Test products in appetite rating studies are often not well-characterized. In this study, special efforts were taken to characterize dietary fibre content and structure in the different test products. Processing had only small effects on the dietary fibre content of breads made from whole or milled rye kernels. However, there was slightly higher total dietary fibre content in bread made from milled rye kernels, probably a result of higher resistant starch formation in the crumb during bread-making . These mThe fact that both of the rye porridges induced satiety more than the reference bread confirmed results from previous studies ,21. BothIn the present study, the weight and volume of the milled kernel porridge was three-fold that of the kernel porridge, resulting in an immediate peak in satiety ratings. An effect that soon disappeared and the two rye porridges had similar effects on satiety during the morning hours. In the afternoon, milling of the rye ingredient seemed to affect appetite, as the whole kernel porridge resulted in a stronger satiety, reduced hunger and reduced desire to eat compared with the milled kernel porridge. Except for the slightly higher resistant starch content in the milled kernel porridge, all other dietary fibre components were similar. Thus, the effects can be solely related to structure.The mechanism by which the intact kernel porridge induced satiety in the afternoon may be by reducing small intestinal digestion and absorption by forming a physical barrier to digestive enzymes , hypotheThe present study showed significant differences in appetite ratings for up to 8 h after intake of different breakfast meals. In order to do this, there was a need to standardize energy intake during the whole period of measure. Therefore ad libitum energy intake could not be included in the study design, at least not in the 8-h period after breakfast, which would be most relevant. Appetite ratings have however previously repeatedly been shown to correlate to and predict voluntary energy intake -33.Future studies should explore whether the satiating effect of rye products is persistent over time and if a diet rich in rye products could facilitate weight control.This study demonstrates a satiety enhancing effect of whole grain rye foods, breads as well as porridges, compared to an iso-caloric sifted wheat bread. Further, an interesting effect regarding the influence of cereal grain structure was discovered. A breakfast meal including whole rye kernels, resulted in increased feelings of satiety in the afternoon, compared to porridge made of whole grain rye flour. The understanding of the underlying mechanisms to the late response several hours after intake is likely to involve colonic events and requires further investigation. Altogether, the findings show that whole grain rye products improve satiety and lower hunger ratings. This may explain how diets rich in whole grain and dietary fibre protect against overweight.The study was supported by the supplier of the material used to make the test products, Lantmännen. HI and HF are employed by Lantmännen R&D, the research and development department of the Lantmännen Group. The authors declare that the data presented in this publication represent a complete, true and faithful representation of the work performed.HI, RA, HF, JO and PÅ designed the study. HI recruited the subjects and performed the study. AR carried out the dietary fibre characterization. RA and HI analyzed the appetite data. HI and AR wrote the first draft of the manuscript. All authors participated in revising the manuscript, read and approved the final manuscript.


To the Editor: The genus Bartonella contains several recently described species, many of which are emerging human pathogens. Human infections are mostly due to Bartonella henselae and B. quintana. Like many vectorborne disease agents, Bartonella species have a natural cycle. This cycle contains a reservoir host, in which Bartonella species cause an intraerythrocytic bacteremia, and a vector, which transmits the bacteria from the reservoir host to a new susceptible host   and B. henselae (one isolate), by internal transcribed spacer amplification and sequencing  and Mékambo and Ekata (seven villages) during July and August 2003. Each dog brought by its owner for the study was weighed and sedated by injection with 50 μg/kg of medetomidine . After the dog was examined, a blood sample was drawn from the jugular vein by Vacutainer . Each dog was tattooed with an identification number and given both antihelminthic and external antiparasitic treatments. During the examination, the dogs were treated with care; upon completion of the examination, the dogs were given 250 μg/kg of the reversal agent atipamezola  intramuscularly. A physical examination form and a questionnaire were completed for each test participant by its owner. A total of 258 dogs  were examined and had blood samples drawn during the study. All animals were of mixed breeds and were 6 months to 14 years old (average 3 years 1 month). The Vacutainer tubes were kept on ice until blood samples were dispensed into cryotubes and frozen in liquid nitrogen. Samples were stored at –80°C until isolation attempts were made on Columbia agar  as described previously (B. vinsonii subsp. berkhoffii was the first Bartonella species found in dogs (B. clarridgeiae (,B. washoensis (Bartonella species was also detected in the DNA of B. henselae (,B. clarridgeiae (B. elizabethae (Bartonella species is not surprising, since Ctenocephalides felis, the vector of B. henselae in cats, has a wide range of hosts, including the domestic dog. However, attempts to isolate this species in samples collected from 211 dogs in the United Kingdom failed (Bartonella species are supposedly difficult to isolate in dogs because of a low concentration of bacteria in the blood (B. henselae, we identified two to four bacterial colonies per milliliter of blood.Bartonella have been obtained in the United States and Europe. Increasingly, Bartonella infections are being reported in Africa, especially in southern Africa (B. henselae from a dog and the first isolation of B. clarridgeiae in Central Africa. That dogs also act as reservoirs of B. henselae likely has implications in Africa where HIV infections are prevalent.Most of the data pertaining to


Attention deficit hyperactivity disorder (ADHD) and its possible causes still attract controversy. Genes, pre and perinatal risks, psychosocial factors and environmental toxins have all been considered as potential risk factors.This review  critically considers putative risk factors with a focus on genetics and selected environmental risks, examines their relationships with ADHD and discusses the likelihood that these risks are causal as well as some of the main implications.No single risk factor explains ADHD. Both inherited and noninherited factors contribute and their effects are interdependent. ADHD is familial and heritable. Research into the inherited and molecular genetic contributions to ADHD suggest an important overlap with other neurodevelopmental problems, notably, autism spectrum disorders. Having a biological relative with ADHD, large, rare copy number variants, some small effect size candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity have been most consistently found as risk factors, but none are yet known to be definitely causal. There is a large literature documenting associations between ADHD and a wide variety of putative environmental risks that can, at present, only be regarded as correlates. Findings from research designs that go beyond simply testing for association are beginning to contest the robustness of some environmental exposures previously thought to be ADHD risk factors.The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history. There is a need to consider the possibility of parents and siblings being similarly affected and how this might impact on engagement with families, influence interventions and require integration with adult services. Genetic contributions to disorder do not necessarily mean that medications are the treatment of choice. We also consider how findings might influence the conceptualisation of ADHD, public health policy implications and why it is unhelpful and incorrect to dichotomise genetic/biological and environmental explanations. It is essential that practitioners can interpret genetic and aetiological research findings and impart informed explanations to families. Despite still periodically attracting public controversy, attention deficit hyperactivity disorder (ADHD) has long been recognised as a clinical entity . In the This is a narrative review, focusing on literature in the last 15 years, selected from a PubMed search. The key words used were ADHD and genetic, inherited, gene-environment interaction, gene-environment interplay, aetiology, linkage, genome-wide association study, copy number variant, twin studies, adoption studies, COMT, conduct disorder, candidate gene, environment, toxins, lead, polychlorinated biphenyls, PCB, pesticides, diet, prenatal, perinatal, pregnancy, smoking, tobacco, substance, stress, birth weight and prematurity. We supplemented these with reviews and book chapters and emphasise replicated findings.Attention deficit hyperactivity disorder, like other psychiatric and developmental disorders runs in families. Genetic risk when passed on from parents is known as inherited risk/liability; not all genetic risks are necessarily inherited (see later). First degree relatives of those with ADHD are two to eight times more likely than relatives of unaffected individuals to also show ADHD . Twin stAdoption studies allow separation of inherited and postnatal environmental effects by examining the degree of concordance or similarity between individuals who have ADHD and their biologically related and unrelated relatives. All five published adoption studies of ADHD  are consFinally, as we will keep emphasising, the issue is never genes or biology versus environment given that there is overwhelming evidence that their effects are so closely intertwined . The mosADHD shows comorbidity with a wide variety of problems . There aHowever, ADHD also shows a high level of comorbidity with other psychiatric and behavioural disorders, notably conduct problems/antisocial behaviour, alcohol and substance misuse and mood disorders, that is explained by shared heritability . Thus, tGenetics is not much different from other aetiological research, in that it involves testing for a relationship between variation in a risk/predictor measure and an outcome. New technologies are, however, allowing for the more detailed capture of genetic variation. For common, complex disorders, such as ADHD, the predominant starting assumption has been that risk is mainly explained by multiple common gene variants of small effect size as well as environmental risks. Family-based linkage study findings have not been consistent with a more simplistic ‘major gene effect model’.The earliest studies of ADHD involved testing for association between disorder and variants in candidate genes selected because they were thought likely to be involved in the pathophysiology of ADHD. Multiple candidate gene association studies of ADHD have been published see . There ip = 5 × 10−8) for genome-wide significance. The statistical threshold is set high because of the multiple testing burden . However, it is now apparent that none of these studies was adequately sized. To date, the largest meta-analysis includes fewer than 3000 ADHD cases. Studies of other disorders  have required thousands and tens of thousands of affected individuals for associated SNPs to reach statistical significance.One of the rationales for undertaking genetic studies is to discover previously unidentified risk pathways. This has led to ‘hypothesis-free’ whole genome searches for common genetic variants (SNPs) that tagged much  genetic variation. Detailed accounts of such genome-wide association studies (GWAS) findings and methods are described elsewhere . GWAS thThere are mixed opinions on the value of such studies. On the one hand, identifying common gene variants that uncover novel biological risk pathways underlying psychiatric disorder is attractive and potentially important. The aim is for this to be achieved by assembling much larger ADHD sample sizes through international collaborations and by performing exome (genetic coding regions) and whole genome sequencing to capture all DNA sequence variation and structural variants  rather than common genetic variants to neuropsychiatric disorders, the effects of which have needed to be very large to be detected. It is has long been recognised that rare chromosomal microdeletion syndromes, such as 22q11 microdeletion syndrome , that involve a deletion encompassing many genes, can lead to increased risk of ADHD and psychosis . Even moIt is now frequently recommended that clinical genetics services should screen for CNVs in individuals with idiopathic ID . HoweverThe earliest CNV studies of ADHD did not find an increased burden of rare CNVs, but suggested disruption of neurodevelopmental pathways . More reAs previously highlighted, as would be expected for any risk factor for a complex disorder (e.g. smoking and ischaemic heart disease), the risk factor (herein a higher burden of large rare CNVs) was not found in all children with ADHD and was present in controls  that is the primary mechanism for breakdown of dopamine in the prefrontal cortex. This gene variant modifies COMT enzyme activity whereby those with the val/val genotype have a higher activity version of the enzyme and breakdown dopamine more rapidly. This gene variant has been found to be associated with conduct disorder symptoms in two clinical studies of ADHD  metabolites of organophosphates and ADHD diagnosis in middle childhood and early adolescence found that those with detectable urinary dimethyl alkylphosphate (DMAP) metabolite concentrations above the median level had double the odds of ADHD in contrast with those with untraceable levels . More stPolychlorinated biphenyls (PCBs) are toxic manufactured organochlorine congeners, which were once mass-produced for a variety of industrial and commercial uses and now persist as environmental contaminants. Both human and importantly, animal studies have found that PCB exposure leads to impairments in working memory, response inhibition and cognitive flexibility – neurobehavioural effects, which are comparable with those seen in ADHD . FurtherAs with PCBs, human and animal studies of lead exposure have looked at effects on cognitive domains relevant to ADHD; cognitive flexibility, vigilance and alertness have been found to be most dependably affected . An assoIt is worth noting that there is evidence that both prenatal exposure to PCBs  is clearly clinically important with regards to clinical management, but care is needed in ascribing direction of effects, causality and potential blame.As already highlighted, genes and environment do not work independently of each other see . Twin anCOMT association with antisocial behaviour in ADHD as possibly being mediated via impaired social understanding.At present, there are no clinical impacts of the molecular genetic findings. Identified genetic risks on their own have small effect sizes or are very rare and are unlikely to be useful in a predictive or diagnostic sense beyond what can already be predicted by a family history. One exception to where genetic testing might be helpful in the future is for children with intellectual disability who have ADHD and other neurodevelopmental disorders . One of When families ask about genetic contributions, it is important that they realise familial and genetic risks only increase the probability of ADHD and do not determine the presence of disorder. Heritability estimates refer to populations and do not mean for example that 90% of an individual’s ADHD is caused by genes.Like other complex disorders, ADHD is not explained by any single risk factor alone and not all those who are exposed to a given risk show disorder. Its occurrence is not explained by inherited factors alone and the pattern of results suggests the contribution of multiple inherited and noninherited factors to its aetiology.In terms of associations with inherited and noninherited factors and adverse consequences, ADHD appears to behave like a trait measure (hyperactivity-impulsiveness and inattentiveness) akin to blood pressure/hypertension; rather than as a qualitatively discrete category. The empirical evidence in favour of using dimensional modifiers in research and practice has been recently highlighted . EvidencGiven ADHD is familial and heritable, for those seeing children with ADHD, the possibility that a parent/parents might be similarly affected and how this might impact on parenting and the intervention plan  needs to be considered e.g. . Also, wThis could require close working with adult services that will increasingly be required to deal with adult neurodevelopmental problems.Identifying a genetic contribution does not necessarily mean that only biological treatments or medication will be effective. At present, multimodal interventions are recommended for ADHD . MoreoveAt present, there are no clear-cut causal environmental risks that have been identified, with the possible exception of extreme early adversity in some rare instances. There are a number of candidates that require further investigation, but it is critical to use designs that go beyond simply assessing correlations. Nevertheless, there are clear health benefits of mothers not smoking, misusing alcohol and drugs and reducing stress levels in pregnancy, for example, because of causal links with birth weight and prematurity. However, the evidence so far suggests that these risks might not play a direct causal role in ADHD. Similarly, good prenatal and later diet, limiting exposure to toxins is a generally sensible approach. However, if these are not true causal risks, exclusively focusing on them as a means of reducing population rates of ADHD will not be sufficient and could distract from searching for and tackling other potentially modifiable risks.Finally, a key message of this review for practitioners and families is that there is overwhelming evidence that the polarisation between genetic/biological and environmental factors, perpetuated by some due to misinterpretation of aetiological and genetics research in relation to complex disorders, is incorrect and unhelpful. Indeed, they are complementary rather than competing explanations.There is no single risk factor that explains ADHD. Many different risks and risk pathways may all lead to the same clinical phenotype.Both inherited and noninherited factors contribute to ADHD, and their effects are interdependent.The most consistently found risk factors for ADHD include having a relative with the disorder, large rare CNVs, candidate gene variants, extreme early adversity, pre and postnatal exposure to lead and low birth weight/prematurity.The risk factors implicated in ADHD tend to have small effect sizes or are rare. They also may increase risk of many other types of psychopathology.It is important to remember that associations between ADHD and investigated risk factors may not necessarily be due to causal effects.There is important overlap with other neurodevelopmental problems, including autistic spectrum disorders, as well as comorbidity with other psychiatric and behavioural disorders.Further genetic studies, that are adequately sized, may be useful in allowing DNA sequence variation and structural variants for ADHD to be captured.Future studies into environmental risk factors associated with ADHD need to use designs that go beyond assessing correlation and look for evidence of causal links.For children with ADHD, the possibility that a parent might be similarly affected needs to be considered, and studies looking at how this may impact on the intervention and outcome for the child, could provide important information for future management.


It is now generally agreed that there are inherent sex differences in healthy individuals across a number of neurobiological domains . Moreover, there is a burgeoning body of evidence highlighting sex differences within neuropsychiatric populations . Here, we consider the extent to which attention and impulsivity are sexually dimorphic in healthy populations and the extent to which sex might modulate the expression of disorders characterised by abnormalities in attention and/or impulsivity such as attention deficit hyperactivity disorder (ADHD), autism and addiction. We then discuss general genetic mechanisms that might underlie sex differences in attention and impulsivity before focussing on specific positional and functional candidate sex-linked genes that are likely to influence these cognitive processes. Identifying novel sex-modulated molecular targets should ultimately enable us to develop more effective therapies in disorders associated with attentional/impulsive dysfunction. Sex difThere is perhaps even more compelling evidence for sexual dimorphic features in many neuropsychiatric disorders, notably in terms of their incidence, their clinical features and progression, and in their underlying pathology . A large2All animals live in a world of competing, multiple and simultaneous stimuli that must be resolved in order so that they behave adaptively. Attention represents the ability to select from a plethora of stimuli, responses, memories and thoughts, and in doing so, disregard any that are behaviourally irrelevant ; ‘attentAs with attention, a single definition that encapsulates all aspects of impulsivity has so far proved elusive  and thisNumerous studies investigating the neuroanatomical circuitry of impulsivity have demonstrated the key role that the frontal cortex plays in humans . This isd-amphetamine) can be used to treat disorders of impulsivity such as ADHD  differ considerably between the sexes in terms of their development and ongoing function  than ADHD males, but greater intellectual impairments and more internalising problems  . In contConsistent evidence for sex differences in brain structure/function within ADHD cohorts has been limited , in agre4.2per se, it is estimated that 30–80% of ASD children meet symptom criteria for ADHD (Autism spectrum disorders (ASDs) are characterised by abnormalities in social function and communication, excessive anxiety and high levels of repetitiveness . As withfor ADHD . ASDs difor ADHD  and it hfor ADHD . Whilst for ADHD  and poorfor ADHD  than thefor ADHD .Addictive behaviours, such as gambling and drug abuse, can be conceptualised as impulsive choices, whereby smaller, immediate rewards are favoured over larger, delayed rewards . Patholo5Ultimately, sex differences in behaviour and cognition must stem from the fact that the two sexes inherit different chromosomal complements: males inherit one cognition-gene rich X chromosome (invariably from their mother) , and a YMultiple lines of evidence have suggested a strong genetic component to attention and impulsivity phenotypes, including data from family, twin and adoption studies for disorders of attention/impulsivity such as ADHD , and theEvidence for the involvement of sex-linked genes specifically in mediating altered attention/impulsivity phenotypes has come from a combination of comparing males and females on measures of attention/impulsivity (described above), studying cohorts with unusual sex chromosome constitutions, from studying individuals with discrete mutations on the X or Y chromosomes, from linkage/association studies and from work in animal models. For example, using an elegant animal model, the so-called ‘four-core genotypes’ cross in which the direct effects of sex-linked genes on neurobiology may be dissociated from their downstream effects on gonadal hormone-mediated effects on neurobiology , it has There are three general mechanisms through which genes on the sex chromosomes may influence sex-specific neurobiology . First, de novo mutation of the Y chromosome  and ADHD suggests the possibility that over-dosage of Y-linked genes on the short arm and/or absence of Y-linked genes on the long arm could be important in mediating ADHD vulnerability  may result in abnormal attentional and/or impulsivity phenotypes. Subjects with such chromosomal abnormalities are relatively rare and their phenotype varies considerably, and as such, data from such studies should be treated with a degree of caution. Males with multiple Y chromosomes, and therefore over-dosage of Y-linked genes , have been reported to exhibit relatively high rates of attentional deficits (distractibility) and ADHD . These frability .Evidence for X-linked gene dosage being important in mediating attentional/impulsive function has come from studying subjects with Turner syndrome  and Klinefelter syndrome . Both of these disorders present with endocrinological abnormalities , so any 6SRY, STS and MAOA represent clear positional and/or functional candidates for effects on attentional and impulsive behaviours. For instance, SRY, either directly via neural expression or indirectly through downstream effects on gonadal hormone levels, may mediate dopaminergic effects linked with attention and impulsivity  (SRY gene is a Y-linked gene (Yp11.3)  which encodes a protein with a DNA-binding motif. This protein acts as a transcription factor in the bipotential gonad of the developing fetus to induce gene expression changes which facilitate differentiation into testicular tissues  (MAOA (the X-linked gene encoding the enzyme monoamine oxidase involved in monoamine breakdown)  . SRY gen tissues . Once fo tissues . Besides tissues ; these a tissues . In man,thalamus ; it is loxylase)  and for eakdown) ; the fac in vivo .SRY could potentially also act as an indirect mediator of attention/impulsivity via its downstream effects on testosterone secretion. Testosterone levels may influence attention/impulsivity in individuals with attentional/impulsive dysfunction  suggested that one of the genes on this chromosome could influence attention. The most promising candidate gene on the basis of its function, and the fact that it was already known to escape X-inactivation, was STS, encoding the enzyme steroid sulfatase (STS gene is X-linked (Xp22.3), escapes X-inactivation  show visuospatial attentional deficits, reduced levels of impulsive action (as indexed by performance on mouse variants of the 5-CSRT and SSRT tasks), elevated levels of aggression and increased locomotor activity  encodes the mitochondrial enzyme monoamine oxidase A (MAOA)  it may partially escape X-inactivation in some tissues in humans; however, the data for this from studies using fibroblasts and hybrid cell work are inconclusive (The X-linked A (MAOA) ; this enA (MAOA) . The abinclusive , and no MAOA gene in mice results in enhanced aggression (MAOA polymorphisms (including the 30 base pair variable number tandem repeat sequence near the promoter) and vulnerability to ADHD (MAOB (Xp11.23) encoding the enzyme monoamine oxidase B , may also influence attention/impulsivity phenotypes and vulnerability to ADHD  inactivating mutations within the gene may lead to extreme impulsiveness and aggression in males , whilst gression , (ii) cegression , (iii) a to ADHD ; these a to ADHD  and (iv) to ADHD . There i to ADHD , althougsiveness .7SRY acting as a transcriptional activator for the autosomal TH gene), or by the downstream pathways influenced by sex-linked genes such as gonadal hormone systems. One interesting gene in this regard is COMT (22q11.21) which encodes the enzyme catechol-O-methyltransferase. COMT was implicated as a candidate gene for ADHD based on its high frontal cortex expression, its absence in ADHD-prone 22q11 deletion syndrome patients, and its role in catecholamine metabolism  allele conferred risk of ADHD in boys, whereas possessing the valine  allele conferred risk of developing ADHD in girls (O-methyltransferase activity is greater in male prefrontal cortex (COMT homozygous knockout male mice have a twofold increase in dopamine levels in the prefrontal cortex compared with male wildtypes, whereas no such discrepancy occurs between female knockout mice and their wildtype counterparts (This review has focussed on sex-linked genetic mechanisms that may underlie attentional and impulsive phenotypes in mammals. However, there are without doubt a large number of autosomal genes whose products are likely to affect the phenotypes of interest here. It is possible that the expression/function of such autosomal genes may be modulated by sex, either by the products of sex-linked genes directly (e.g. tabolism . Most stin girls . In furtin girls . The idel cortex  and thatterparts .8There is persuasive evidence that the sexes differ with respect to their relative vulnerability to disorders of attention and impulsivity. Moreover, there is putative evidence that healthy males and females show differences in their attentional and impulsive profiles, and in the brain structures underlying these cognitive processes. However, these latter findings are, at present, inconsistent and the field requires further exploration. These sex differences in neurobiology must be underpinned by genes on the X and Y chromosomes exerting their effects by either direct action in the brain or via intermediary mechanisms such as systemic hormone secretion; here, we have reviewed several plausible mechanisms via which genes on the sex chromosomes may influence attention and impulsivity.a priori rather than analysing data from males and females a posteriori. Additional useful work in humans might focus upon identifying potential regions of interest underlying attention/impulsivity phenotypes on the X chromosome using large scale linkage or association or copy number variant analyses, although the idiosyncratic nature of this chromosome makes it difficult to study using standard methods (Future work, utilising state-of-the-art imaging techniques, should try to specify more accurately the neuropsychological and neuroanatomical differences that distinguish healthy males and females, male/female controls from their counterparts presenting with disorders of attention or impulsivity, controls from subjects with sex chromosome anomalies, and controls from subjects with mutations within specific sex-linked genes. To achieve the first two objectives, sex difference studies should ideally be planned  methods . Finally methods  and to e