53 resultados para [4.3.0]bicyclic antisense nucleoside


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A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (net iAUC) = 22.9 ± 6.8 pg/mL × 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 ± 0.5 mmol/L × 6 h vs. 6.0 ± 0.5 mmol/L × 6 h, P = 0.015) but not in the normal-weight group (4.3 ± 0.5 mmol/L × 6 h vs. 4.8 ± 0.5 mmol/L × 6 h, P = 0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068.

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Accurate assessments of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere is important to better understand the global carbon cycle, support the climate policy process, and project future climate change. Present-day analysis requires the combination of a range of data, algorithms, statistics and model estimates and their interpretation by a broad scientific community. Here we describe datasets and a methodology developed by the global carbon cycle science community to quantify all major components of the global carbon budget, including their uncertainties. We discuss changes compared to previous estimates, consistency within and among components, and methodology and data limitations. CO2 emissions from fossil fuel combustion and cement production (EFF) are based on energy statistics, while emissions from Land-Use Change (ELUC), including deforestation, are based on combined evidence from land cover change data, fire activity in regions undergoing deforestation, and models. The global atmospheric CO2 concentration is measured directly and its rate of growth (GATM) is computed from the concentration. The mean ocean CO2 sink (SOCEAN) is based on observations from the 1990s, while the annual anomalies and trends are estimated with ocean models. Finally, the global residual terrestrial CO2 sink (SLAND) is estimated by the difference of the other terms. For the last decade available (2002–2011), EFF was 8.3 ± 0.4 PgC yr−1, ELUC 1.0 ± 0.5 PgC yr−1, GATM 4.3 ± 0.1 PgC yr−1, SOCEAN 2.5 ± 0.5 PgC yr−1, and SLAND 2.6 ± 0.8 PgC yr−1. For year 2011 alone, EFF was 9.5 ± 0.5 PgC yr−1, 3.0 percent above 2010, reflecting a continued trend in these emissions; ELUC was 0.9 ± 0.5 PgC yr−1, approximately constant throughout the decade; GATM was 3.6 ± 0.2 PgC yr−1, SOCEAN was 2.7 ± 0.5 PgC yr−1, and SLAND was 4.1 ± 0.9 PgC yr−1. GATM was low in 2011 compared to the 2002–2011 average because of a high uptake by the land probably in response to natural climate variability associated to La Niña conditions in the Pacific Ocean. The global atmospheric CO2 concentration reached 391.31 ± 0.13 ppm at the end of year 2011. We estimate that EFF will have increased by 2.6% (1.9–3.5%) in 2012 based on projections of gross world product and recent changes in the carbon intensity of the economy. All uncertainties are reported as ±1 sigma (68% confidence assuming Gaussian error distributions that the real value lies within the given interval), reflecting the current capacity to characterise the annual estimates of each component of the global carbon budget. This paper is intended to provide a baseline to keep track of annual carbon budgets in the future.

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AIMS HIV infection may be associated with an increased recurrence rate of myocardial infarction. Our aim was to determine whether HIV infection is a risk factor for worse outcomes in patients with coronaray artery disease. METHODS We compared data aggregated from two ongoing cohorts: (i) the Acute Myocardial Infarction in Switzerland (AMIS) registry, which includes patients with acute myocardial infarction (AMI), and (ii) the Swiss HIV Cohort Study (SHCS), a prospective registry of HIV-positive (HIV+) patients. We included all patients who survived an incident AMI occurring on or after 1st January 2005. Our primary outcome measure was all-cause mortality at one year; secondary outcomes included AMI recurrence and cardiovascular-related hospitalisations. Comparisons used Cox and logistic regression analyses, respectively. RESULTS There were 133 HIV+, (SHCS) and 5,328 HIV-negative [HIV-] (AMIS) individuals with incident AMI. In the SHCS and AMIS registries, patients were predominantly male (72% and 85% male, respectively), with a median age of 51 years (interquartile range [IQR] 46-57) and 64 years (IQR 55-74), respectively. Nearly all (90%) of HIV+ individuals were on successful antiretroviral therapy. During the first year of follow-up, 5 (3.6%) HIV+ and 135 (2.5%) HIV- individuals died. At one year, HIV+ status after adjustment for age, sex, calendar year of AMI, smoking status, hypertension and diabetes was associated with a higher risk of death (HR 4.42, 95% CI 1.73-11.27). There were no significant differences in recurrent AMIs (4 [3.0%] HIV+ and 146 [3.0%] HIV- individuals, OR 1.16, 95% CI 0.41-3.27) or in hospitalization rates (OR 0.68 [95% CI 0.42-1.11]). CONCLUSIONS HIV infection was associated with a significantly increased risk of all-cause mortality one year after incident AMI.

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PURPOSE To systematically evaluate the dependence of intravoxel-incoherent-motion (IVIM) parameters on the b-value threshold separating the perfusion and diffusion compartment, and to implement and test an algorithm for the standardized computation of this threshold. METHODS Diffusion weighted images of the upper abdomen were acquired at 3 Tesla in eleven healthy male volunteers with 10 different b-values and in two healthy male volunteers with 16 different b-values. Region-of-interest IVIM analysis was applied to the abdominal organs and skeletal muscle with a systematic increase of the b-value threshold for computing pseudodiffusion D*, perfusion fraction Fp , diffusion coefficient D, and the sum of squared residuals to the bi-exponential IVIM-fit. RESULTS IVIM parameters strongly depended on the choice of the b-value threshold. The proposed algorithm successfully provided optimal b-value thresholds with the smallest residuals for all evaluated organs [s/mm2]: e.g., right liver lobe 20, spleen 20, right renal cortex 150, skeletal muscle 150. Mean D* [10(-3) mm(2) /s], Fp [%], and D [10(-3) mm(2) /s] values (±standard deviation) were: right liver lobe, 88.7 ± 42.5, 22.6 ± 7.4, 0.73 ± 0.12; right renal cortex: 11.5 ± 1.8, 18.3 ± 2.9, 1.68 ± 0.05; spleen: 41.9 ± 57.9, 8.2 ± 3.4, 0.69 ± 0.07; skeletal muscle: 21.7 ± 19.0; 7.4 ± 3.0; 1.36 ± 0.04. CONCLUSION IVIM parameters strongly depend upon the choice of the b-value threshold used for computation. The proposed algorithm may be used as a robust approach for IVIM analysis without organ-specific adaptation. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

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Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere is important to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe data sets and a methodology to quantify all major components of the global carbon budget, including their uncertainties, based on the combination of a range of data, algorithms, statistics and model estimates and their interpretation by a broad scientific community. We discuss changes compared to previous estimates, consistency within and among components, alongside methodology and data limitations. CO2 emissions from fossil-fuel combustion and cement production (EFF) are based on energy statistics, while emissions from land-use change (ELUC), mainly deforestation, are based on combined evidence from land-cover change data, fire activity associated with deforestation, and models. The global atmospheric CO2 concentration is measured directly and its rate of growth (GATM) is computed from the annual changes in concentration. The mean ocean CO2 sink (SOCEAN) is based on observations from the 1990s, while the annual anomalies and trends are estimated with ocean models. The variability in SOCEAN is evaluated for the first time in this budget with data products based on surveys of ocean CO2 measurements. The global residual terrestrial CO2 sink (SLAND) is estimated by the difference of the other terms of the global carbon budget and compared to results of independent dynamic global vegetation models forced by observed climate, CO2 and land cover change (some including nitrogen–carbon interactions). All uncertainties are reported as ± 1 σ, reflecting the current capacity to characterise the annual estimates of each component of the global carbon budget. For the last decade available (2003–2012), EFF was 8.6 ± 0.4 GtC yr − 1, ELUC 0.9 ± 0.5 GtC yr − 1, GATM 4.3 ± 0.1 GtC yr − 1, S OCEAN 2.5 ± 0.5 GtC yr − 1, and S LAND 2.8 ± 0.8 GtC yr − 1. For year 2012 alone, EFF grew to 9.7 ± 0.5 GtC yr − 1, 2.2 % above 2011, reflecting a continued growing trend in these emissions, GATM was 5.1 ± 0.2 GtC yr − 1, SOCEANwas 2.9 ± 0.5 GtC yr −1, and assuming an ELU Cof 1.0 ± 0.5 GtC yr − 1 (based on the 2001–2010 average), SLAND was 2.7 ± 0.9 GtC yr − 1. GATM was high in 2012 compared to the 2003–2012 average, almost entirely reflecting the high EFF. The global atmospheric CO2 con- centration reached 392.52 ± 0.10 ppm averaged over 2012. We estimate that EFF will increase by 2.1 % (1.1–3.1 %) to 9.9 ± 0.5 GtC in 2013, 61 % above emissions in 1990, based on projections of world gross domestic product and recent changes in the carbon intensity of the economy. With this projection, cumulative emissions of CO2 will reach about 535 ± 55 GtC for 1870–2013, about 70 % from EFF (390 ± 20 GtC) and 30 % from ELUC (145 ± 50 GtC). This paper also documents any changes in the methods and data sets used in this new carbon budget from previous budgets (Le Quéré et al., 2013). All observations presented here can be downloaded from the Carbon Dioxide Information Analysis Center.

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BACKGROUND Traditional approaches for nighttime glycemic control in glycogen storage disease type I (GSDI) include continuous tube feeding, or ingestion of uncooked corn starch (CS) at bedtime. A modified corn starch (MCS) has been shown to prolong euglycemia in some patients. The aim of this study was to evaluate whether stable nighttime glucose control can be achieved with other types of slowly digested carbohydrates in adult GSDI patients. METHODS In this cross-over study, nocturnal glucose control and fasting times were assessed with three different nocturnal nutrition regimens in five patients, using continuous glucose monitoring (CGMS) in an outpatient everyday life setting. For each patient, continuous glucose profiles were measured after ingestion of (1) CS, (2) MCS or (3) a pasta meal at bedtime, during 5 to 6 consecutive nights for each regimen. RESULTS Stable nocturnal glucose control was achieved for all patients with a pasta meal, with a mean duration of glycemia >3.5 mmol/l of 7.6 h (range 5.7-10.8), and >4 mmol/l of 7 h (5.2-9.2), similar to CS and MCS. Fasting glucose before breakfast on workdays (after 7.1 ± 0.8 h) was not significantly different between the three interventions (CS 4.1 ± 0.5 mmol/l, MCS 4.6 ± 0.7 mmol/l, pasta 4.3 ± 0.9 mmol/l). During prolonged fasting on weekends, longer duration of normoglycemia was achieved with CS or MCS than with pasta. CONCLUSION Consumption of cooked pasta is a suitable and more palatable alternative to uncooked corn starch to achieve nighttime glucose control in adult patients with GSDI.

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Background The accumulation of mutations after long-lasting exposure to a failing combination antiretroviral therapy (cART) is problematic and severely reduces the options for further successful treatments. Methods We studied patients from the Swiss HIV Cohort Study who failed cART with nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The loss of genotypic activity <3, 3–6, >6 months after virological failure was analyzed with Stanford algorithm. Risk factors associated with early emergence of drug resistance mutations (<6 months after failure) were identified with multivariable logistic regression. Results Ninety-nine genotypic resistance tests from PI/r-treated and 129 from NNRTI-treated patients were analyzed. The risk of losing the activity of ≥1 NRTIs was lower among PI/r- compared to NNRTI-treated individuals <3, 3–6, and >6 months after failure: 8.8% vs. 38.2% (p = 0.009), 7.1% vs. 46.9% (p<0.001) and 18.9% vs. 60.9% (p<0.001). The percentages of patients who have lost PI/r activity were 2.9%, 3.6% and 5.4% <3, 3–6, >6 months after failure compared to 41.2%, 49.0% and 63.0% of those who have lost NNRTI activity (all p<0.001). The risk to accumulate an early NRTI mutation was strongly associated with NNRTI-containing cART (adjusted odds ratio: 13.3 (95% CI: 4.1–42.8), p<0.001). Conclusions The loss of activity of PIs and NRTIs was low among patients treated with PI/r, even after long-lasting exposure to a failing cART. Thus, more options remain for second-line therapy. This finding is potentially of high relevance, in particular for settings with poor or lacking virological monitoring.

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Study Design. In vitro study to develop an intervertebral disc degeneration (IDD) organ culture model, using coccygeal bovine intervertebral discs (IVDs) and injection of proteolytic enzymes MMP-3, ADAMTS-4 and HTRA1.Objective. This study aimed to develop an in-vitro model of enzyme-mediated IDD to mimic the clinical outcome in humans for investigation of therapeutic treatment options.Summary of Background Data. Bovine IVDs are comparable to human IVDs in terms of cell composition and biomechanical behavior. Researchers injected papain and trypsin into them to create an IDD model with a degenerated nucleus pulposus (NP) area. They achieved macroscopic cavities as well as a loss of glycosaminoglycans (GAGs). However, none of these enzymes are clinically relevant.Methods. Bovine IVDs were harvested maintaining the endplates. Active forms of MMP-3, ADAMTS-4 and HTRA1 were injected at a dose of 10μg/ml each. Phosphate buffered saline (PBS) was injected as a control. Discs were cultured for 8 days and loaded diurnally (day 1 to day 4 with 0.4 MPa for 16 h) and left under free swelling condition from day 4 to day 8 to avoid expected artifacts due to dehydration of the NP. Outcome parameters included disc height, metabolic cell activity, DNA content, glycosaminoglycan (GAG) content, total collagen content, relative gene expression and histological investigation.Results. The mean metabolic cell activity was significantly lower in the NP area of discs injected with ADAMTS-4 compared to the day 0 control discs. Disc height was decreased following injection with HTRA1, and was significantly correlated with changes in GAG/DNA of the NP tissue. Total collagen content tended to be lower in groups injected with ADAMTS4 and MMP-3.Conclusion. MMP-3, ADAMTS-4 and HTRA1 neither provoked visible matrix degradation nor major shifts in gene expression. However, cell activity was significantly reduced and HTRA1 induced loss of disc height which positively correlated with changes in GAG/DNA content. The use of higher doses of these enzymes or a combination thereof may therefore be necessary to induce disc degeneration

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We re-analyze the signal of non-planetary energetic neutral atoms (ENAs) in the 0.4-5.0 keV range measured with the Neutral Particle Detector (NPD) of the ASPERA-3 and ASPERA-4 experiments on board the Mars and Venus Express satellites. Due to improved knowledge of sensor characteristics and exclusion of data sets affected by instrument effects, the typical intensity of the ENA signal obtained by ASPERA-3 is an order of magnitude lower than in earlier reports. The ENA intensities measured with ASPERA-3 and ASPERA-4 now agree with each other. In the present analysis, we also correct the ENA signal for Compton-Getting and for ionization loss processes under the assumption of a heliospheric origin. We find spectral shapes and intensities consistent with those measured by the Interstellar Boundary Explorer (IBEX). The principal advantage of ASPERA with respect to the IBEX sensors is the two times better spectral resolution. In this study, we discuss the physical significance of the spectral shapes and their potential variation across the sky. At present, these observations are the only independent test of the heliospheric ENA signal measured with IBEX in this energy range. The ASPERA measurements also allow us to check for a temporal variation of the heliospheric signal as they were obtained between 2003 and 2007, whereas IBEX has been operational since the end of 2008.

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BACKGROUND: Chlorhexidine (CHX) rinsing after periodontal surgery is common. We assessed the clinical and microbiological effects of two CHX concentrations following periodontal surgery. MATERIALS AND METHODS: In a randomized, controlled clinical trial, 45 subjects were assigned to 4 weeks rinsing with a 0.05 CHX/herbal extract combination (test) or a 0.1% CHX solution. Clinical and staining effects were studied. Subgingival bacteria were assessed using the DNA-DNA checkerboard. Statistics included parametric and non-parametric tests (p<0001 to declare significance at 80% power). RESULTS: At weeks 4 and 12, more staining was found in the control group (p<0.05 and p<0.001, respectively). A higher risk for staining was found in the control group (crude OR: 2.3:1, 95% CI: 1.3 to 4.4, p<0.01). The absolute staining reduction in the test group was 21.1% (9 5% CI: 9.4-32.8%). Probing pocket depth (PPD) decreases were significant (p<0.001) in both groups and similar (p=0.92). No rinse group differences in changes of bacterial counts for any species were found between baseline and week 12. CONCLUSIONS: The test CHX rinse resulted in less tooth staining. At the study endpoint, similar and high counts of periodontal pathogens were found.

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BACKGROUND: Periodontitis has been associated with cardiovascular disease. We assess if the recurrence of acute coronary syndrome (ACS) could be predicted by preceding medical and periodontal conditions. METHODS: A total of 165 consecutive subjects with ACS and 159 medically healthy, matched control subjects were examined and followed for 3 years. Periodontitis was defined by alveolar bone loss. Subgingival microbial samples were studied by the checkerboard DNA-DNA hybridization method. RESULTS: The recurrence of ACS was found in 66 of 165 (40.0%) subjects, and a first ACS event was found in seven of 159 (4.4%) subjects among baseline control subjects. Subjects who later had a second ACS event were older (P <0.001). Significantly higher serum levels of high-density lipoprotein (P <0.05), creatinine (P <0.01), and white blood cell (WBC) counts (P <0.001) were found in subjects with future ACS. Periodontitis was associated with a first event of ACS (crude odds ratio [OR]: 10.3:1; 95% confidence interval [CI]: 6.1 to 17.4; P <0.001) and the recurrence of ACS (crude OR: 3.6:1; 95% CI: 2.0 to 6.6; P <0.001). General linear modeling multivariate analysis, controlling for age and the prediction of a future ACS event, identified that WBC counts (F = 20.6; P <0.001), periodontitis (F = 17.6; P <0.001), and serum creatinine counts (F = 4.5; P <0.05) were explanatory of a future ACS event. CONCLUSIONS: The results of this study indicate that recurrent ACS events are predicted by serum WBC counts, serum creatinine levels, and a diagnosis of periodontitis. Significantly higher counts of putative pathogens are found in subjects with ACS, but these counts do not predict future ACS events.

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A high resolution luminescence study of NaLaF4: 1%Pr3+, 5%Yb3+ and NaLaF4: 1%Ce3+, 5%Yb3+ in the UV to NIR spectral range using a InGaAs detector and a fourier transform interferometer is reported. Although the Pr3+(P-3(0) -> (1)G(4), Yb3+(F-2(7/2) -> F-2(5/2)) energy transfer step takes place, significant Pr3+ (1)G(4) emission around 993, 1330 and 1850 nm is observed. No experimental proof for the second energy transfer step in the down-conversion process between Pr3+ and Yb3+ can be given. In the case of NaLaF4: Ce3+, Yb3+ it is concluded that the observed Yb3+ emission upon Ce3+ 5d excitation is the result of a charge transfer process instead of down-conversion. (C) 2010 Elsevier B.V. All rights reserved.

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Purpose: The objective of this review was to systematically screen the literature for data related to the survival and complication rates observed with dental or implant double crown abutments and removable prostheses under functional loading for at least 3 years. Materials and Methods: A systematic review of the dental literature from January 1966 to December 2009 was performed in electronic databases (PubMed and Embase) as well as by an extensive hand search to investigate the clinical outcomes of double crown reconstructions. Results: From the total of 2412 titles retrieved from the search, 65 were selected for full-text review. Subsequently, 17 papers were included for data extraction. An estimation of the cumulative survival and complication rates was not feasible due to the lack of detailed information. Tooth survival rates for telescopic abutment teeth ranged from 82.5% to 96.5% after an observation period of 3.4 to 6 years, and for tooth-supported double crown retained dentures from 66.7% to 98.6% after an observation period of 6 to 10 years. The survival rates of implants were between 97.9% and 100% and for telescopic-retained removable dental prostheses with two mandibular implants, 100% after 3.0 and 10.4 years. The major biological complications affecting the tooth abutments were gingival inflammation, periodontal disease, and caries. The most frequent technical complications were loss of cementation and loss of facings. Conclusions: The main findings of this review are: (I) double crown tooth abutments and dentures demonstrated a wide range of survival rates. (II) Implant-supported mandibular overdentures demonstrated a favorable long-term prognosis. (III) A greater need for prosthetic maintenance is required for both tooth-supported and implant-supported reconstructions. (IV) Future areas of research would involve designing appropriate longitudinal studies for comparisons of survival and complication rates of different reconstruction designs.

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Children with attention-deficit/hyperactivity disorder (ADHD) have a higher rate of obesity than children without ADHD. Obesity risk alleles may overlap with those relevant for ADHD. We examined whether risk alleles for an increased body mass index (BMI) are associated with ADHD and related quantitative traits (inattention and hyperactivity/impulsivity). We screened 32 obesity risk alleles of single nucleotide polymorphisms (SNPs) in a genome-wide association study (GWAS) for ADHD based on 495 patients and 1,300 population-based controls and performed in silico analyses of the SNPs in an ADHD meta-analysis comprising 2,064 trios, 896 independent cases, and 2,455 controls. In the German sample rs206936 in the NUDT3 gene (nudix; nucleoside diphosphate linked moiety X-type motif 3) was associated with ADHD risk (OR: 1.39; P = 3.4 × 10(-4) ; Pcorr  = 0.01). In the meta-analysis data we found rs6497416 in the intronic region of the GPRC5B gene (G protein-coupled receptor, family C, group 5, member B; P = 7.2 × 10(-4) ; Pcorr  = 0.02) as a risk allele for ADHD. GPRC5B belongs to the metabotropic glutamate receptor family, which has been implicated in the etiology of ADHD. In the German sample rs206936 (NUDT3) and rs10938397 in the glucosamine-6-phosphate deaminase 2 gene (GNPDA2) were associated with inattention, whereas markers in the mitogen-activated protein kinase 5 gene (MAP2K5) and in the cell adhesion molecule 2 gene (CADM2) were associated with hyperactivity. In the meta-analysis data, MAP2K5 was associated with inattention, GPRC5B with hyperactivity/impulsivity and inattention and CADM2 with hyperactivity/impulsivity. Our results justify further research on the elucidation of the common genetic background of ADHD and obesity.