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Angle is an important concept in geometry. Young children have difficulty separating angle size from other dimensions such as the length of angle sides, perhaps due to whole-object bias in word learning. The present study used the pre-test-training-post-test design to investigate the effectiveness of two ways of separating angle from angle size in 3-6-year-old Chinese preschoolers. A total of 228 children were given a pre-test and 219 of them failed the crucial test. 168 of the 219 children were present at school during the training phase and were randomly assigned to three groups: the "toma" group (n = 57), which received training to call the whole angle figure as "toma" and angle size as angle size; the "angle/angle size" group (n = 56), which received the training of separating "angle" from "angle size"; and the control group (n = 55), which used "angle size" alone to represent both the overall angle figure and angle size. Results showed that the "toma" group improved significantly more than the other two groups, the latter of which did not differ from each other. These results suggest that it is insufficient to have two separate words/phrases (angle and angle size) for children to learn to differentiate angle from angle size, perhaps due to their shared usage of the word angle. Instead, the use of a novel term is necessary and sufficient to improve learning. Implications for preschool education are discussed.

[This corrects the article DOI: 10.3389/fpsyg.2020.563493.].

Wantai Dang,1,&ast; Xiaohui Xu,2,&ast; Danling Luo,2 Hui Luo,2 Jin Hu,2 Jingguo Zhou,1 Jian Liu,2 Lanlan You2 1Department of Rheumatism and Immunity, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China; 2Department of Ultrasound, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lanlan You Email 17027279@qq.comObjective: To explore the effects of different blood uric acid levels in gout patients on the two-dimensional image of the kidney and the risk factors for gout-related kidney damage for providing clinical evidence to enable early prevention and treatment of gout-related kidney damage.Methods: We obtained information of 227 patients with primary gout and estimated the association between two-dimensional kidney images and clinical indicators using binary logistic regression.Results: Our study showed that different uric acid levels, age, disease course, cystatin C (CysC) level, and γ-glutamyl transpeptidase level were correlated with echo of the renal medulla (P < 0.05). CysC level was correlated with the renal cortex thickness and kidney stones in different uric acid-level groups (P < 0.05). Disease course, aspartate transaminase (AST) level, creatinine (CREA) level, and tophi were risk factors for renal cortex thinning in gout patients (P = 0.045, 0.026, 0.004, 0.006, respectively). The disease course, platelet (PLT) count, and high-density lipoprotein (HDL-C) level were risk factors for kidney stone formation in gout patients (P = 0.037, 0.022, 0.023, respectively), while CysC level and C-reactive protein (CRP) level were risk factors for increased renal medulla echo in these patients (P = 0.022, 0.028, respectively).Conclusion: Our study revealed disease course, AST level, CREA level, tophi, PLT c

Block building is a popular play activity among young children and is also used by psychologists to assess their intelligence. However, little research has attempted to systematically explore the cognitive bases of block-building ability. The current study (N = 66 Chinese preschoolers, 32 boys and 34 girls; mean age = 4.7 years, SD = 0.29, range = 3.4 to 5.2 years) investigated the relationships between six measures of spatial skills (shape naming, shape recognition, shape composition, solid figure naming, cube transformation, and mental rotation, with the former four representing form perception and the latter two representing visualization) and block-building complexity. Correlation results showed that three of the four measures of form perception (shape naming, shape recognition, and shape composition) were significantly and positively correlated with block-building complexity, whereas the two measures of visualization were not. Results from regression models indicated that shape recognition and shape composition, as well as shape-recognition-by-gender interaction, were unique predictors of children's block-building complexity. These findings provide preliminary evidence for the basic spatial skills underlying children's block-building complexity and have implications for classroom instructions aimed at improving preschoolers' block-building complexity.

Odontocetes have evolved for millions of years to own a unique echolocation system. The exceptional performance of odontocetes echolocation system can provide reference to artificial sonar systems, acoustic metamaterials and sound control designs. Research on odontocetes biosonar requires interdisciplinary effort, including acoustics, biology, biomimetics, anatomy, physiology and signal analysis. In this paper, we review odontoctes’ biosonar emission process from aspects of anatomy, biosonar signal and beam formation. To begin, computed tomography scanning and untrasound measurements are combined to reconstruct the sound speed and density distributions. To follow, efforts are thrown to probe into the biosonar signal and its corresponding acoustic behavior. Numerical simulations are used to investigate the odontocetes’ biosonar beam formation. The secret of exceptional performance of odontocetes’ echolocation system lies in their unique anatomy. Odontocete integrates acoustic structures with different acoustic impedances, namely solid bony structures, air space and soft tissues as a whole emission system to efficiently modulate sound propagation and sound beam formation. These acoustic structures are well organized in the forehead, forming a natural acoustic metamaterial to perform a good control of sounds. These results can enlighten artificial sonar designs.

Zhenyu Wang1 *, Wenhao Shen1 *, Xugang Li,2 Yang Feng,1 Kun Qian,1 Gaoren Wang,3 Yiying Gao,1 Xiaohui Xu,4 Shuyu Zhang,1 Ling Yue,1 Jianping Cao1 1School of Radiation Medicine and Protection (SRMP) of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Suzhou 215123, People’s Republic of China; 2Department of Radiotherapy, Anshan Cancer Hospital, Anshan 114036, People’s Republic of China; 3Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong 226361, People’s Republic of China; 4Department of General Surgery, The First People’s Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou 215400, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianping Cao; Ling Yue Tel +86-512-65880037Email jpcao@suda.edu.cn; yueling@suda.edu.cnPurpose: As radiation therapy is widely used for the management of pancreatic cancer, identifying novel targets to improve the radiosensitivity of cancer cells is beneficial. Rosiglitazone, a specific peroxisome proliferator-activated receptor γ (PPARγ) agonist, has an inhibitory effect on various types of cancer cells. The purpose of this paper is to investigate the effect of rosiglitazone on the radiosensitivity of pancreatic cancer cells and the potential mechanism.Materials and Methods: PPARγ expression in pancreatic cancer and adjacent tissues was evaluated using immunohistochemistry analysis. The viability, migration and invasion ability of PANC1 and PaTu8988 cells were detected using MTT assay, scratch-wound assay and transwell invasion assay. The effect of rosiglitazone on radiosensitivity of the cells was determined using the clonogenic assay. PANC1 cells were inoculated into BALB/c mice to establish tumors. Microarray was used to investigate changes of genes involved.Results: Higher PPARγ expression was demonstrated in pancreatic can

Luhui Qin,1,2,* Xiaolin Zhang,1,* Xing Zhou,1 Xingchun Wu,1 Xiang Huang,1 Ming Chen,1 Yani Wu,1 Shunyu Lu,1 Hongliang Zhang,1 Xiaohui Xu,1 Xiaojie Wei,1 Shijun Zhang,1 Renbin Huang1 1Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Center for Translational Medicine, Key Laboratory of Longevity and Aging-Related Diseases, Ministry of Education, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Renbin Huang; Shijun ZhangPharmaceutical College, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, People’s Republic of ChinaTel +86 771 533 9805Fax +86 771 535 8272Email huangrenbin518@163.com; gxykdxzsj@163.comBackground: Studies have demonstrated that the roots of Averrhoa carambola L. (Oxalidaceae), a traditional Chinese medicine, can be used to treat diabetes and diabetes-related diseases. Nevertheless, the potential beneficial effects and mechanism of benzoquinone isolated from the roots of Averrhoa carambola L. (BACR) on diabetes remain unclear.Methods: Diabetic Kunming mice were injected with STZ (120 mgkg− 1) in the tail vein. Fasting blood glucose (FBG) and the change of body weight were measured after oral administration of BACR (120, 60, 30 mg/kg/d) every week. The levels of the total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), glucosylated hemoglobin (GHb), fasting insulin (FINS), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. The histological examination of pancreatic tissues and the TLR4/NF-κB pathway was analyzed by RT-PCR, immunohistochemistry and Western blot.Results: The study found that clearly the BACR obviously reduced the blood glucose, serum lipids, GHb and FINS. In addition, BACR treatment markedly reduced the release of inflammatory factors, includin

Xiaohui Xu,1,2,* Biao Chen,3,* Qichun Huang,1 Yani Wu,4 Tao Liang5 1Department of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 2Institute of Cancer Prevention and Treatment of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, People’s Republic of China; 3The First Nanning People’s Hospital, Nanning, Guangxi 530022, People’s Republic of China; 4Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China; 5College of Stomatology of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohui XuDepartment of Pharmacy, Affiliated Tumor Hospital of Guangxi Medical University, No. 71, Hedi Road, Nanning 530021, People’s Republic of ChinaTel/ Fax +86 771-5778582Email 1056112307@qq.comTao LiangCollege of Stomatology of Guangxi Medical University, No. 10, Shuangyong Road, Nanning 530021, People’s Republic of ChinaTel/ Fax +86 771-5358635Email kqliangtao@126.comBackground and Purpose: Autophagy is the main protective mechanism against aging in podocytes, which are terminally differentiated cells that have a very limited capacity for mitosis and self-renewal. Here, a streptozotocin-induced DN C57BL/6 mouse model was used to investigate the effects of puerarin on the modulation of autophagy under conditions associated with endoplasmic reticulum stress (ERS). In addition, this study aimed to identify the potential underlying molecular mechanisms.Methods and Results: DN C57BL/6 mouse model was induced by streptozotocin (150 mg/kg) injection. The mice were administered rapamycin and puerarin, respectively, daily for up to 8 weeks. After the serum and kidney samples were collected, the fasting blood glucose (FBG), parameters of renal function, histomorphology, and the podocyte functional pr

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Bioinspiration & Biomimetics 14 (2019): 016004, doi:10.1088/1748-3190/aaeb01., Sound transmission and reception are both vital components to odontocete echolocation and daily life. Here, we combine computed tomography (CT) scanning and Finite Element Modeling to investigate the acoustic propagation of finless porpoise (Neophocaena asiaorientalis sunameri) echolocation pulses. The CT scanning and FEM wave propagation model results support the well-accepted jaw-hearing pathway hypothesis and suggest an additional alternative auditory pathway composed of structures, mandible (lower jaw) and internal mandibular fat, with different acoustic impedances, which may also conduct sounds to the ear complexes. The internal mandibular fat is attached to the ear complex and encased by the mandibles laterally and anteriorly. The simulations show signals in this pathway initially propagate along the solid mandibles and are transmitted to the acoustically coupled soft tissue of the internal mandibular fat which conducts the stimuli posteriorly as it eventually arrives at ear complexes. While supporting traditional theories, this new bone-tissue-conduction pathway might be meaningful to understand the hearing and sound reception processes in a wide variety of odontocetes species., This work is financially supported in part by the National Natural Science Foundation of China (Grants No. 41276040, No. 11174240, and No. 41676023) and the Natural Science Foundation of Fujian Province of China (Grant No. 2012J06010).

PurposeClinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria.MethodsIn this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule.ResultsPretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole.ConclusionsThe co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Esterases receive special attention because of their wide distribution in biological systems and environments and their importance for physiology and chemical synthesis. The prediction of esterases’ substrate promiscuity level from sequence data and the molecular reasons why certain such enzymes are more promiscuous than others remain to be elucidated. This limits the surveillance of the sequence space for esterases potentially leading to new versatile biocatalysts and new insights into their role in cellular function. Here, we performed an extensive analysis of the substrate spectra of 145 phylogenetically and environmentally diverse microbial esterases, when tested with 96 diverse esters. We determined the primary factors shaping their substrate range by analyzing substrate range patterns in combination with structural analysis and protein–ligand simulations. We found a structural parameter that helps rank (classify) the promiscuity level of esterases from sequence data at 94% accuracy. This parameter, the active site effective volume, exemplifies the topology of the catalytic environment by measuring the active site cavity volume corrected by the relative solvent accessible surface area (SASA) of the catalytic triad. Sequences encoding esterases with active site effective volumes (cavity volume/SASA) above a threshold show greater substrate spectra, which can be further extended in combination with phylogenetic data. This measure provides also a valuable tool for interrogating substrates capable of being converted. This measure, found to be transferred to phosphatases of the haloalkanoic acid dehalogenase superfamily and possibly other enzymatic systems, represents a powerful tool for low-cost bioprospecting for esterases with broad substrate ranges, in large scale sequence data sets.

Feng Guo, Zhiyong Zhang, Yushang Cui, Li Li, Xiaohui Xu, Shanqing Li Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China Introduction: Acquired benign esophageal tracheobronchial fistulae are clinically rare. In this paper, we summarize our experiences in surgical treatment of 14 consecutive patients with acquired benign esophageal tracheobronchial fistula.Methods: This series included patients who underwent surgery between January 2002 and June 2015 at our institution. We retrieved and analyzed data on demographics, operative characteristics, and surgical outcome of the patients.Results: Bronchofiberscopy revealed the membranous trachea openings of fistulae and gastroendoscopy further showed lesions in the anterolateral wall of the esophagus. Thoracotomy, division of the fistulous tract, and closure of the esophagus and trachea and other procedures were performed. All operations were uneventful, and there was no perioperative and postoperative complication or death. Symptoms disappeared after surgery in patients. The median length of hospital stay was 53 (range 31–270) days. The patients were followed up for a median of 33.5 (range 15–168) months. No recurrence was reported.Conclusion: Our results suggest that acquired benign esophageal tracheobronchial fistulae have a broad spectrum of anatomic pathologies and exhibit markedly varied clinical manifestations, and a surgical approach tailored to the condition of individual patients is recommended. Keywords: esophageal tracheobronchial fistula, surgery, safety

Although much is known about the development of mental representations of numbers, it is not clear how early children begin to represent numbers on a linear scale. The current study aimed to examine the development of numerical estimation of Chinese preschoolers. In total, 160 children of three age groups (51 3- and 4-year-olds, 50 5-year-olds, and 59 6-year-olds) were administered the numerical estimation task on three types of number lines (Arabic numbers, dots, and objects). All three age groups took the test on the 0-10 number lines, and the oldest group also took it on the 0-100 and 0-1000 Arabic number lines. Results showed that (a) linear representation of numbers increased with age, (b) representation of numbers was consistent across the three types of tasks, (c) Chinese participants generally showed earlier onset of various landmarks of attaining linear representations (e.g., linearity of various number ranges, accuracy, intercepts) than did their Western counterparts, as reported in previous studies, and (d) the estimates of older Chinese preschoolers on the 0-100 and 0-1000 symbolic number lines fitted the two-linear and linear models better than alternative models such as the one-cycle, two-cycle, and logarithmic models. These results extend the small but accumulating literature on the earlier development of number cognition among Chinese preschoolers compared with their Western counterparts, suggesting the importance of cultural factors in the development of early number cognition.

DUF89 family proteins occur widely in both prokaryotes and eukaryotes, but their functions are unknown. Here we define three DUF89 subfamilies (I, II, and III), with subfamily II being split into stand-alone proteins and proteins fused to pantothenate kinase (PanK). We demonstrated that DUF89 proteins have metal-dependent phosphatase activity against reactive phosphoesters or their damaged forms, notably sugar phosphates (subfamilies II and III), phosphopantetheine and its S-sulfonate or sulfonate (subfamily II-PanK fusions), and nucleotides (subfamily I). Genetic and comparative genomic data strongly associated DUF89 genes with phosphoester metabolism. The crystal structure of the yeast (Saccharomyces cerevisiae) subfamily III protein YMR027W revealed a novel phosphatase active site with fructose 6-phosphate and Mg(2+) bound near conserved signature residues Asp254 and Asn255 that are critical for activity. These findings indicate that DUF89 proteins are previously unrecognized hydrolases whose characteristic in vivo function is to limit potentially harmful buildups of normal or damaged phosphometabolites.

Background The direct isolation of integron gene cassettes from cultivated and environmental microbial sources allows an assessment of the impact of the integron/gene cassette system on the emergence of new phenotypes, such as drug resistance or virulence. A structural approach is being exploited to investigate the modularity and function of novel integron gene cassettes. Methodology/Principal Findings We report the 1.8 A crystal structure of Cass2, an integron-associated protein derived from an environmental V. cholerae. The structure defines a monomeric beta-barrel protein with a fold related to the effector-binding portion of AraC/XylS transcription activators. The closest homologs of Cass2 are multi-drug binding proteins, such as BmrR. Consistent with this, a binding pocket made up of hydrophobic residues and a single glutamate side chain is evident in Cass2, occupied in the crystal form by polyethylene glycol. Fluorescence assays demonstrate that Cass2 is capable of binding cationic drug compounds with submicromolar affinity. The Cass2 module possesses a protein interaction surface proximal to its drug-binding cavity with features homologous to those seen in multi-domain transcriptional regulators. Conclusions/Significance Genetic analysis identifies Cass2 to be representative of a larger family of independent effector-binding proteins associated with lateral gene transfer within Vibrio and closely-related species. We propose that the Cass2 family not only has capacity to form functional transcription regulator complexes, but represents possible evolutionary precursors to multi-domain regulators associated with cationic drug compounds., National Health and Medical Research Council (Australia) (NHMRC grant 488502), National Institutes of Health (U.S.) (Grant GM62414-0 ), Ontario. Ministry of Revenue (Challenge Fund)

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3′ untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains.

It is important to enable reasoning about the meaning and possible effects of updates to ensure that the updated system operates correctly. A formal, mathematical model of dynamic update should be developed, in order to understand by both users and implementors of update technology what design choices can be considered. In this paper, we define a formal calculus $update\pi$, a variant extension of higher-order $\pi$ calculus, to model dynamic updates of component-based software, which is language and technology independent. The calculus focuses on following main concepts: proper granularity of update, timing of dynamic update, state transformation between versions, update failure check and recovery. We describe a series of rule on safe component updates to model some general processes of dynamic update and discuss its reduction semantics coincides with a labelled transition system semantics that illustrate the expressive power of these calculi., Comment: 11 pages

The environment plays an important role in the health of communities. However, few health systems exist at the state and/or local levels to efficiently track the potential health effects associated with environmental exposure. The objectives of this dissertation are 1) to use secondary data for assessing the possible associations between health outcomes and environmental exposure and/or hazard; 2) to explore possible methods of data linkage and analyses which can be used by state and local environmental health tracking agencies and 3) to bring positive contributions to the development of national Environmental Public Health Tracking Network (EPHT). In this project, the Three Mile Island (TMI) cohort data (1979-1995) and Pennsylvania (PA) Cancer registry data were used to evaluate the associations between cigarette smoking and adult leukemia. A case-crossover analysis was performed with PA cardiopulmonary hospital admission data and local air pollution data to assess the health effects of air pollutants on cardiopulmonary disease before and after the elimination of a major point source of air pollution. A case-control study was also conducted to examine the associations between term low birth weight and particulate air pollution. The results showed that cigarette smoking could increase the risk of acute myeloid leukemia (AML). In addition, particulate air pollution is significantly associated with cardiovascular hospitalization and low birth weight in term infant. In conclusion, the findings suggest that environmental hazards have adverse health effects on a number of health endpoints. Secondary data can be a great resource for environmental public health tracking, which is of public health relevance. The use of existing data is an effective way to assess the potential health effects associated with environmental exposures after an appropriate study design with a feasible data linkage and correct methods of data analyses was developed.

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood behavioral disorder. Identifying risk factors for ADHD may lead to improved intervention and prevention. The dopamine transporter gene (DAT1) is associated with ADHD in several studies, with an average 1.2 odds ratio and evidence of heterogeneity across data sets. OBJECTIVE: To investigate sources of heterogeneity by refining the DAT1 association using additional markers and investigating gene-environment interaction between DAT1 and maternal use of alcohol and tobacco during pregnancy. DESIGN: Prospective study. SETTING AND PATIENTS: Children with ADHD from child behavior clinics in the southeast of England and in the Taipei area of Taiwan. INTERVENTIONS: Within-family tests of association using 2 repeat polymorphisms in the 3' untranslated region and intron 8 plus additional markers in the English sample. MAIN OUTCOME MEASURES: Transmission ratios of risk alleles from heterozygote parents to affected offspring and comparison of the transmission ratios in high- and low-exposure groups for the environmental variables. RESULTS: A novel association was identified between ADHD, the intron 8 polymorphism, and a specific risk haplotype in both English and Taiwanese samples. The risk haplotype showed significant interactions with maternal use of alcohol during pregnancy. CONCLUSIONS: The identification of a common haplotype in 2 independent populations is an important step toward identifying functionally significant regions of DAT1. Interaction between DAT1 genotypes and maternal use of alcohol during pregnancy suggests that DAT1 moderates the environmental risk and has implications for the prevention of ADHD. Further studies are required to delineate the precise causal risk factor involved in this interaction.

It has been widely postulated that the categorical diagnosis of attention deficit hyperactivity disorder (ADHD) should be seen as the extreme end of a set of traits quantitatively distributed in the general population. A consequence of this is that the genes associated with DSM-IV ADHD should also influence these underlying traits in non-affected individuals. The aim of this study was to examine if specific candidate loci previously shown to be associated with DSM-IV ADHD, also act as quantitative trait loci (QTLs) for ADHD-symptoms in the general population. We have genotyped five candidate markers in a population-based sample of male dizygous twin-pairs (n = 329 pairs). We found little evidence to support a role for the previously-nominated alleles of a DRD4 VNTR, a 5HT1B SNP, or a microsatellite marker near to DRD5, in the distribution of ADHD-symptoms scores; however, we found some evidence to suggest that the DAT1 3'UTR VNTR and weak evidence that a microsatellite in SNAP-25 may have a role in continuous measures of ADHD-symptoms hyperactivity above and beyond their role in clinical ADHD.

The norepinephrine system is known to play a role in attentional and cognitive-energetic mechanisms and is thought to be important in attention deficit hyperactivity disorder (ADHD). Stimulant medications are known to alter the activity of norepinephrine as well as dopamine in the synapse and the highly selective norepinephrine reuptake inhibitor, atomoxetine, is an effective treatment for ADHD symptoms. This study set out to investigate whether common polymorphisms within the norepinephrine transporter gene (NET1) are associated with DSM-IV ADHD combined subtype, using a sample that has previously shown association with genes that affect the synaptic release and uptake of neurotransmitters; DAT1 and SNAP-25. We identified 21 single nucleotide polymorphisms (SNPs) from publicly available databases that had minor allele frequencies > or =5% and span the NET1 genomic region, including those analyzed in previous studies of ADHD. DNA pooling was used to screen for associations using two case pools (n = 180 cases) and four control pools (n = 334 controls). We identified three SNPs that showed suggestive evidence for association using either case-control or within family tests of association, however, none of these were significant after adjustment for the number of markers analyzed. We conclude that none of the markers show significant evidence of association with ADHD although we cannot rule out small genetic effects.