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Removal of synaptically-released glutamate by astrocytes is necessary to spatially and temporally limit neuronal activation. Recent evidence suggests that astrocytes may have specialized functions in specific circuits, but the extent and significance of such specialization are unclear. By performing direct patch-clamp recordings and two-photon glutamate imaging, we report that in the somatosensory cortex, glutamate uptake by astrocytes is slower during sustained synaptic stimulation when compared to lower stimulation frequencies. Conversely, glutamate uptake capacity is increased in the frontal cortex during higher frequency synaptic stimulation, thereby limiting extracellular buildup of glutamate and NMDA receptor activation in layer 5 pyramidal neurons. This efficient glutamate clearance relies on Na + /K + -ATPase function and both GLT-1 and non-GLT-1 transporters. Thus, by enhancing their glutamate uptake capacity, astrocytes in the frontal cortex may prevent excessive neuronal excitation during intense synaptic activity. These results may explain why diseases associated with network hyperexcitability differentially affect individual brain areas., Competing Interests: The authors declare no competing interests.

This work investigates the effects of neutron irradiation on nitrogen and hydrogen adsorption in boron-doped activated carbon. Boron-neutron capture generates an energetic lithium nucleus, helium nucleus, and gamma photons, which can alter the surface and structure of pores in activated carbon. The defects introduced by fission tracks are modeled assuming the slit-shaped pores geometry. Sub-critical nitrogen adsorption shows that nitrogen molecules cannot probe the defects created by fission tracks. Hydrogen adsorption isotherms of irradiated samples indicate higher binding energies compared to their non-irradiated parent samples.

An overview is given of the development of sorbent materials for hydrogen storage. Understanding the surface properties of the adsorbed film is crucial to optimize hydrogen storage capacities. In this work, the lattice gas model (Ono-Kondo) is used to determine the properties of the adsorbed hydrogen film from a single supercritical hydrogen isotherm at 77 K. In addition, this method does not require a conversion between gravimetric excess adsorption and absolute adsorption. The overall average binding energy of hydrogen is 4.4 kJ/mol and the binding energy at low coverage is 9.2 kJ/mol. The hydrogen film density at saturation is 0.10 g/mL corresponding to a local pressure of 1500 bar in the adsorbed phase.

The complex structure of activated carbon can be described as a three-dimensional network of graphene layers oriented in random directions. In this work, we propose a new model of the microporous structure, taking into account the degree of activation. We derive a structural relation between porosity, skeletal density, specific surface area, and the number of graphitic blocks per unit volume. In addition, we present a new approach to evaluate the interdependency between porosity and specific surface area by combining high-resolution scanning transmission electron microscopy and subcritical nitrogen adsorption. Finally, we propose a structural metric that predicts the relation between the volumetric storage capacity and the gravimetric storage capacity of supercritical methane at room temperature., Competing Interests: The authors declare no competing financial interest.

Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy., Competing Interests: Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons. Conditional deletion of Dag1, encoding dystroglycan, in pyramidal cells caused loss of CCK-positive basket cell terminals in hippocampus and neocortex. PV-positive basket cell terminals were unaffected in mutant mice, demonstrating interneuron subtype-specific function of dystroglycan. Loss of dystroglycan in pyramidal cells had little influence on clustering of other GABAergic postsynaptic proteins and of glutamatergic synaptic proteins. CCK-positive terminals were not established at P21 in the absence of dystroglycan and were markedly reduced when dystroglycan was ablated in adult mice, suggesting a role for dystroglycan in both formation and maintenance of CCK-positive terminals. The necessity of neuronal dystroglycan for functional innervation by CCK-positive basket cell axon terminals was confirmed by reduced frequency of inhibitory events in pyramidal cells of dystroglycan-deficient mice and further corroborated by the inefficiency of carbachol to increase IPSC frequency in these cells. Finally, neurexin binding seems dispensable for dystroglycan function because knock-in mice expressing binding-deficient T190M dystroglycan displayed normal CCK-positive terminals. Together, we describe a novel function of dystroglycan in interneuron subtype-specific trans-synaptic signaling, revealing correlation of presynaptic and postsynaptic molecular diversity., Significance Statement: Dystroglycan, an extracellular and transmembrane protein of the dystrophin-glycoprotein complex, is at the center of molecular studies of muscular dystrophies. Although its synaptic distribution in cortical brain regions is long established, function of dystroglycan in the synapse remained obscure. Using mice that selectively lack neuronal dystroglycan, we provide evidence that a subset of GABAergic interneurons requires dystroglycan for formation and maintenance of axonal terminals on pyramidal cells. As such, dystroglycan is the first postsynaptic GABAergic protein for which an interneuron terminal-specific function could be shown. Our findings also offer a new perspective on the mechanisms that lead to intellectual disability in muscular dystrophies without associated brain malformations., (Copyright © 2016 the authors 0270-6474/16/3610297-18$15.00/0.)

Type 1 diabetes (T1D) and celiac disease (CeD) cluster in families and can occur in the same individual. Genetic loci have been associated with susceptibility to both diseases. Our aim was to explore the genetic differences between individuals developing both these diseases (double autoimmunity) versus those with only one. We hypothesized that double autoimmunity individuals carry more of the genetic risk markers that are shared between the two diseases independently. SNPs were genotyped in loci associated with T1D (n=42) and CeD (n=28) in 543 subjects who developed double autoimmunity, 2,472 subjects with T1D only, and 2,223 CeD-only subjects. For identification of loci that were specifically associated with individuals developing double autoimmunity, two association analyses were conducted: double autoimmunity versus T1D and double autoimmunity versus CeD. HLA risk haplotypes were compared between the two groups. The CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CeD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5/DQ8, provided the highest risk for developing double autoimmunity (odds ratio 5.22, P=2.25×10(-29)). We identified a strong HLA risk genotype (DQ2.5/DQ8) predisposing to double autoimmunity, suggesting a dominant role for HLA. Non-HLA loci, CTLA4 and IL2RA, may also confer risk to double autoimmunity. Thus, CeD patients who carry the DQ2.5/DQ8 genotype may benefit from periodic screening of autoantibodies related to T1D., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and observed five new associations that account for 18% of the genetic risk. Taking these new loci together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.

Studies in European populations have contributed to a better understanding of the genetics of complex diseases, for example, in coeliac disease (CeD), studies of over 23 000 European samples have reported association to the HLA locus and another 39 loci. However, these associations have not been evaluated in detail in other ethnicities. We sought to better understand how disease-associated loci that have been mapped in Europeans translate to a disease risk for a population with a different ethnic background. We therefore performed a validation of European risk loci for CeD in 497 cases and 736 controls of north Indian origin. Using a dense-genotyping platform (Immunochip), we confirmed the strong association to the HLA region (rs2854275, P=8.2 × 10(-49)). Three loci showed suggestive association (rs4948256, P=9.3 × 10(-7), rs4758538, P=8.6 × 10(-5) and rs17080877, P=2.7 × 10(-5)). We directly replicated five previously reported European variants (P<0.05; mapping to loci harbouring FASLG/TNFSF18, SCHIP1/IL12A, PFKFB3/PRKCQ, ZMIZ1 and ICOSLG). Using a transferability test, we further confirmed association at PFKFB3/PRKCQ (rs2387397, P=2.8 × 10(-4)) and PTPRK/THEMIS (rs55743914, P=3.4 × 10(-4)). The north Indian population has a higher degree of consanguinity than Europeans and we therefore explored the role of recessively acting variants, which replicated the HLA locus (rs9271850, P=3.7 × 10(-23)) and suggested a role of additional four loci. To our knowledge, this is the first replication study of CeD variants in a non-European population.

A main underlying pathology of coronary artery disease is the deposition of cholesterol in the arteries supplying blood to the heart that leads to stenosis and myocardial infarction. We tested if dyslipidemia is a risk factor for coronary artery disease in the Lebanese population, and studied the role of the total cholesterol/HDL cholesterol (TC/HDL-C) ratio as a biological marker of coronary artery disease. We recruited 6,180 Lebanese patients undergoing cardiac catheterization. We conducted a cross-sectional association study between TC/HDL-C ratio and the number and type of vessels occluded in catheterized patients by controlling for confounding effects. The TC/HDL-C ratio ≥4 significantly predicts ≥50 % stenosis in all vessels individually with the odds ratio (OR) ranging from 1.22 to 1.92. The OR increased with increasing number of ≥50 % stenotic vessels (1.39 for 2 vessels and 1.64 for 3-4 vessels), as did risk due to diabetes, CAD family history, gender, and age. The younger than average age of onset subgroup shows a pronounced increase in risk for occlusion of the left main coronary artery due to TC/HDL-C ≥4 (OR 3.26). In conclusion, low levels of HDL-cholesterol and high levels TC/HDL-C ratio are strong biological markers of disease occurrence and severity in the Lebanese population.

Background: There is a lack of adequate prospective data on quality-of-life (QOL) and its predictors in patients undergoing laparoscopic sleeve gastrectomy (LSG). The aim of this study was to assess longitudinal changes in QOL after LSG with the use of the obesity-specific Moorehead-Ardelt II questionnaire (MAII) and to identify clinical parameters associated with QOL outcome., Methods: Morbidly obese patients consecutively admitted for LSG, over a 30-month period, were prospectively studied. QOL was assessed using the validated Greek version of the MAII questionnaire and a visual analogueue scale (VAS), preoperatively and at 6, 12, and 24 months postoperatively. Anthropometric data and obesity-related co-morbidities were recorded., Results: A total of 111 patients with a mean age 36.8±9.2 years were included. Mean preoperative body mass index (BMI) was 49.1±7.5 kg/m2. Percentage excess BMI loss (%EBL) was 51.1±14.9, 64.2±17.9 and 66.4±18.0 at 6, 12, and 24 months, respectively. Postoperatively, all obesity-related co-morbidities were significantly improved. MAII score increased from -.40±1.30 preoperatively to 1.75±.83, 2.18±.80, and 1.95±.71 at 6, 12, and 24 months postoperatively (trend P<.001). Preoperative median (interquartile range) VAS was 3 (1) increasing to 9 (2), 10 (1), and 9 (1) at 6, 12, and 24 months postoperatively (P<.001). %EBL and reduction in obesity-related co-morbidities, especially resolution of diabetes and sleep apnea, correlated significantly with higher QOL during the course of the study., Conclusion: LSG, a safe and effective bariatric operation, results in sustained weight loss and significant improvements in QOL. Both weight loss and amelioration of co-morbidities contribute to higher level of postsurgical QOL., (Copyright © 2015 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are crucial to the understanding of Type 2 Diabetes Mellitus (T2DM) pathophysiology. We report a GWAS on the genetic basis of T2DM in a 3,286 Lebanese participants. More than 5,000,000 SNPs were directly genotyped or imputed using the 1000 Genomes Project reference panels. We identify genome-wide significant variants in two loci CDKAL1 and TCF7L2, independent of sex, age and BMI, with leading variants rs7766070 (OR = 1.39, P = 4.77 × 10(-9)) and rs34872471 (OR = 1.35, P = 1.01 × 10(-8)) respectively. The current study is the first GWAS to find genomic regions implicated in T2DM in the Lebanese population. The results support a central role of CDKAL1 and TCF7L2 in T2DM susceptibility in Southwest Asian populations and provide a plausible component for understanding molecular mechanisms involved in the disease.

Background: A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age., Methods: We performed a multicenter, randomized, double-blind, placebo-controlled dietary-intervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age., Results: Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention., Conclusions: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.).

Objective: The purpose of this study was to explore whether non-human leukocyte antigen (non-HLA) genetic markers can improve type 1 diabetes(T1D) prediction in a prospective cohort with high-risk HLA-DR,DQ genotypes., Methods: The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for the development of T1D and islet autoimmunity (IA)children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms (SNPs) and one microsatellite., Results: In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA [hazard ratio(HR)=1.87, 1.55, and 1.54, respectively, all p ≤ 0.003], while GLIS3 and IL2RA showed borderline association with development of IA. INS,UBASH3A, and IFIH1 were significantly associated with progression from IA to diabetes (HR=1.65, 1.44, and 1.47, respectively, all p ≤ 0.04), while PTPN22 and IL27 showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with PTPN22 rs2476601 TT or HLA-DR3/4 and UBASH3A rs11203203 AA developed diabetes by age 15, compared with 3% of children with all other genotypes (p<0.0001). Addition of non-HLA markers to HLA-DR3/4,DQ8 did not improve diabetes prediction in first-degree relatives., Conclusion: Addition of PTPN22 and UBASH3A SNPs to HLA-DR,DQ genotyping can improve T1D risk prediction., (2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To assess the distribution of human leukocyte antigen (HLA)-DQ2 and -DQ8 in Iranian celiac disease (CD) patients and compare them to healthy Iranian controls., Methods: To predict the HLA-DQA1 and -DQB1 genes, we used six previously reported HLA-tagging single nucleotide polymorphism to determine HLA genotypes in 59 Iranian patients with 'biopsy-confirmed' CD and in 151 healthy Iranian individuals. To test the transferability of the method, 50 cases and controls were also typed using a commercial kit that identifies individual carriers of DQ2, DQ7 and DQ8 alleles., Results: In this pilot study 97% of CD cases (n = 57) and 58% of controls (n = 87) were carriers of HLA-DQ2 and/or HLA-DQ8 heterodimers, either in the homozygous or heterozygous state. The HLA-DQ pattern of these 57 CD patients: heterozygous DQ2.2 (n = 14) and homozygous DQ2.2 (n = 1), heterozygous DQ2.5 (n = 33) and homozygous DQ2.5 (n = 8), heterozygous DQ8 (n = 13) and homozygous DQ8 (n = 2). Two CD patients were negative for both DQ2 and DQ8 (3%)., Conclusion: The prevalence of DQ8 in our CD population was higher than that reported in other populations (25.4%). As reported in other populations, our results underline the primary importance of HLA-DQ alleles in the Iranian population's susceptibility to CD.

Background: The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD., Objective: We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing., Design: We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case-control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals., Results: Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations., Conclusions: Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD.

Lebanon has a highly fragmented health care system. The Lebanese population receives its health care services through a system dominated by the private sector that is dependent to a large extent on public sector financing. Lebanon spends about 83% of its Gross Domestic Product (GDP) on health. This study consists of observations on the utilization of the Ministry of Public Health (MOH) program of hospital care provision. The study population included all patients admitted for hospitalization in any of the 126 hospitals contracted with the MOH, between August 2008 and July 2009 (one full year). This review is limited to medical admissions only. The surgical admissions have been excluded since they are covered under a 'flat fee' reimbursement. Findings reveal that a significant proportion of the hospital admissions under this program are for conditions that may not need hospitalization. Moreover, most of these admissions receive care in relatively small and peripheral hospitals. The findings ought to lead to a further scrutiny of the ministry program of support to the hospitalization of its nationals. Measures may be indicated to improve the efficiency and effectiveness of hospital utilization, avoid waste and possibly fraud, and reconsider the role of small and peripheral hospitals within the health care system of the country.

Background: Resource consumption is a widely used proxy for severity of illness, and is often measured through a case-mix index (CMI) based on Diagnosis Related Groups (DRGs), which is commonly linked to payment. For countries that do not have DRGs it has been suggested to use CMIs derived from International Classification of Diseases (ICD). Our research objective was to use ICD-derived case-mix to evaluate whether or not the current accreditation-based hospital reimbursement system in Lebanon is appropriate., Methods: Our study population included medical admissions to 122 hospitals contracted with the Lebanese Ministry of Public Health (MoPH) between June 2011 and May 2012. Applying ICD-derived CMI on principal diagnosis cost (CMI-ICDC) using weighing similar to that used in Medicare DRG CMI, analyses were made by hospital accreditation, ownership and size. We examined two measures of 30-day re-admission rate. Further analysis was done to examine correlation between principal diagnosis CMI and surgical procedure cost CMI (CMI-CPTC), and three proxy measures on surgical complexity, case complexity and surgical proportion., Results: Hospitals belonging to the highest accreditation category had a higher CMI than others, but no difference was found in CMI among the three other categories. Private hospitals had a higher CMI than public hospitals, and those more than 100 beds had a higher CMI than smaller hospitals. Re-admissions rates were higher in accreditation category C hospitals than category D hospitals. CMI-ICDC was fairly correlated with CMI-CPTC, and somehow correlated with the proposed proxies., Conclusions: Our results indicate that the current link between accreditation and reimbursement rate is not appropriate, and leads to unfairness and inefficiency in the system. Some proxy measures are correlated with case-mix but are not good substitutes for it. Policy implications of our findings propose the necessity for changing the current reimbursement system by including case mix and outcome indicators in addition to accreditation in hospital contracting. Proxies developed may be used to detect miss-use and provider adverse behavior. Research using ICD-derived case mix is limited and our findings may be useful to inform similar initiatives and other limited-setting countries in the region.

Properties of a new class of hypothetical high-surface-area porous carbons (open carbon frameworks) have been discussed. The limits of hydrogen adsorption in these carbon porous structures have been analyzed in terms of competition between increasing surface accessible for adsorption and the lowering energy of adsorption. From an analysis of an analytical model and simulations of adsorption the physical limits of hydrogen adsorption have been defined: (i) higher storage capacities in slit-shaped pores can be obtained by fragmentation/truncation of graphene sheets into nano-metric elements which creates surface areas in excess of 2600 m(2)/g, the surface area for infinite graphene sheets; (ii) the positive influence of increasing surface area is compensated by the decreasing energy of adsorption in the carbon scaffolds of nano-metric sizes; (iii) for open carbon frameworks (OCF) built from coronene and benzene molecules with surface areas 6500 m(2) g(-1), we find an impressive excess adsorption of 75-110 g H2/kg C at 77 K, and high storage capacity of 110-150 g H2/kg C at 77 K and 100 bar; (iv) the new OCF, if synthesized and optimized, could lead to required hydrogen storage capacity for mobile applications.

OBJECTIVE Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. METHOD Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. RESULTS Polygenic risk for ADHD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by the aggression items. CONCLUSIONS Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity.

Background: Controversial results regarding the efficacy and toxicity of hypoxic abdominal and pelvic stop-flow perfusion chemotherapy (SFP) have been reported in relatively small series. Hence, because adequate assessment of its benefit in large homogenous cohorts is missing, acceptable morbidity should initially be assured in a series of adequate size. Additionally, risk factors should be assessed for eventual patient selection., Methods: The morbidity of abdominal and pelvic SFP performed on a miscellaneous group of patients in our institute was analyzed and potential risk factors for adverse events were evaluated., Results: Seventy abdominal (n = 42) and pelvic (n = 28) SFP were performed on 55 patients. In total, 28 adverse effects were observed after 30% of the procedures. Severe (grade 3) adverse events were recorded only after 4% of the procedures, while treatment-related life-threatening events and deaths were not present. Abdominal procedures when compared with pelvic ones were associated with increased systemic toxicity (36 vs. 7%, p = 0.005). Advanced age, gender, prior chemotherapy and/or radiotherapy, limited experience, repeated procedure, drug choice and omission of hemofiltration after SFP completion were not associated with statistically significant increase of procedures with overall or systemic adverse events., Conclusions: In the present series, abdominal and pelvic SFP was associated with an acceptable morbidity, which was mostly mild or moderate. Abdominal procedures were associated with increased toxicity. This procedure seems to be repeatable and also well tolerated both by elderly patients and by patients who had undergone prior chemotherapy and/or radiotherapy, while hemofiltration does not appear to decrease the incidence of systemic toxicity.

A class of high-surface-area carbon hypothetical structures has been investigated that goes beyond the traditional model of parallel graphene sheets hosting layers of physisorbed hydrogen in slit-shaped pores of variable width. The investigation focuses on structures with locally planar units (unbounded or bounded fragments of graphene sheets), and variable ratios of in-plane to edge atoms. Adsorption of molecular hydrogen on these structures was studied by performing grand canonical Monte Carlo simulations with appropriately chosen adsorbent-adsorbate interaction potentials. The interaction models were tested by comparing simulated adsorption isotherms with experimental isotherms on a high-performance activated carbon with well-defined pore structure (approximately bimodal pore-size distribution), and remarkable agreement between computed and experimental isotherms was obtained, both for gravimetric excess adsorption and for gravimetric storage capacity. From this analysis and the simulations performed on the new structures, a rich spectrum of relationships between structural characteristics of carbons and ensuing hydrogen adsorption (structure-function relationships) emerges: (i) Storage capacities higher than in slit-shaped pores can be obtained by fragmentation/truncation of graphene sheets, which creates surface areas exceeding of 2600 m(2)/g, the maximum surface area for infinite graphene sheets, carried mainly by edge sites; we call the resulting structures open carbon frameworks (OCF). (ii) For OCFs with a ratio of in-plane to edge sites ≈1 and surface areas 3800-6500 m(2)/g, we found record maximum excess adsorption of 75-85 g of H(2)/kg of C at 77 K and record storage capacity of 100-260 g of H(2)/kg of C at 77 K and 100 bar. (iii) The adsorption in structures having large specific surface area built from small polycyclic aromatic hydrocarbons cannot be further increased because their energy of adsorption is low. (iv) Additional increase of hydrogen uptake could potentially be achieved by chemical substitution and/or intercalation of OCF structures, in order to increase the energy of adsorption. We conclude that OCF structures, if synthesized, will give hydrogen uptake at the level required for mobile applications. The conclusions define the physical limits of hydrogen adsorption in carbon-based porous structures.

We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children identified as having high-risk HLA-DR/DQ genotypes for type 1 diabetes. Of those, 109 developed IA and 61 progressed to diabetes. Study participants were genotyped for 20 non-HLA polymorphisms, previously confirmed as type 1 diabetes susceptibility loci. PTPN22 and UBASH3A predicted both IA and diabetes in regression models controlling for family history of type 1 diabetes and presence of HLA-DR3/4-DQB1*0302 genotype. In addition, PTPN2 predicted IA whereas INS predicted type 1 diabetes. The final multivariate regression models for both IA and type 1 diabetes included PTPN22, UBASH3A, and INS, in addition to family history of type 1 diabetes and HLA-DR3/4. In general population children, the most frequent combinations including these five significant predictors conferred hazard ratio of up to 13 for IA and >40 for type 1 diabetes. Non-HLA susceptibility alleles may help estimate risk for development of type 1 diabetes in the general population. These findings require replication in different populations.

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology., Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium., Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder., Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

This paper demonstrates that nanospace engineering of KOH activated carbon is possible by controlling the degree of carbon consumption and metallic potassium intercalation into the carbon lattice during the activation process. High specific surface areas, porosities, sub-nanometer (<1 nm) and supra-nanometer (1-5 nm) pore volumes are quantitatively controlled by a combination of KOH concentration and activation temperature. The process typically leads to a bimodal pore size distribution, with a large, approximately constant number of sub-nanometer pores and a variable number of supra-nanometer pores. We show how to control the number of supra-nanometer pores in a manner not achieved previously by chemical activation. The chemical mechanism underlying this control is studied by following the evolution of elemental composition, specific surface area, porosity, and pore size distribution during KOH activation and preceding H(3)PO(4) activation. The oxygen, nitrogen, and hydrogen contents decrease during successive activation steps, creating a nanoporous carbon network with a porosity and surface area controllable for various applications, including gas storage. The formation of tunable sub-nanometer and supra-nanometer pores is validated by sub-critical nitrogen adsorption. Surface functional groups of KOH activated carbon are studied by microscopic infrared spectroscopy.

The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, OR = 1.37, p = 1.57×10(-5)). The association was replicated in an additional 2,547 individuals (OR = 1.31, p = 8.85×10(-6)), leading to genome-wide significant association in a combined analysis (OR = 1.34, p = 8.02×10(-10)). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD.

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) =  1.2 × 10(-12)), rs864537 near CD247 (P(combined) =  2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined) =  2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined) =  1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases., Competing Interests: YL has employment and stock interest in Celera.

Background and Aim: Potential celiacs have the 'celiac type' HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways transform a genetically predisposed individual into an affected person. The aim of the study is to explore the genetic features of Potential CD individuals., Methods: 127 'potential' CD patients entered the study because of positive anti-tissue transglutaminase and no mucosal lesions; about 30% of those followed for four years become frankly celiac. They were genotyped for 13 polymorphisms of 'candidate genes' and compared to controls and celiacs. Moreover, 60 biopsy specimens were used for expression studies., Results: Potential CD bear a lighter HLA-related risk, compared to celiac (χ(2) = 48.42; p value = 1×10(-8)). They share most of the polymorphisms of the celiacs, but the frequency of c-REL* G allele was suggestive for a difference compared to celiac (χ(2) = 5.42; p value = 0.02). One marker of the KIAA1109/IL-2/IL-21 candidate region differentiated potentials from celiac (rs4374642: χ2 = 7.17, p value = 0.01). The expression of IL-21 was completely suppressed in potentials compared to celiacs (p value = 0.02) and to controls (p value = 0.02), in contrast IL-2, KIAA1109 and c-REL expression were over-expressed., Conclusions: Potential CD show genetic features slightly different from celiacs. Genetic and expression markers help to differentiate this condition. Potential CD is a precious biological model of the pathways leading to the small intestinal mucosal damage in genetically predisposed individuals.

Background: PreventCD (www.preventcd.com) is a European multicentre study, which studies the influence of infant nutrition, and that of genetic, immunologic and environmental factors, on the risk of developing coeliac disease (CD). The hypothesis is that it is possible to induce tolerance to gluten by introducing small quantities of gluten to infants, preferably while they are still being breast-fed, and that this might also reduce the risk for related autoimmune disorders., Aim: To describe the design of this ongoing European CD research project., Methods: PreventCD encompasses two study designs and two study populations: (i) a European multicentre study: a prospective, double-blind, randomized dietary-intervention study among infants from families with high risk of CD, and (ii) a Swedish population-based CD screening study among 12-year-olds from the general population, divided into two birth cohorts that differ with respect to infant feeding practices., Discussion: PreventCD is expected to elucidate some of the genetic and immunological mechanisms involved in the process of immune intolerance.

Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed., Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model., Results: No genome-wide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1., Conclusions: The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles., (2010 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Adults with attention-deficit/hyperactivity disorder (ADHD) were examined for early and late attentional processes as a function of controlled attention. The test paradigm was the attentional modulation of prepulse inhibition (PPI; early controlled attentional processing) and prepulse facilitation (PPF; late controlled attentional processing). In 49 patients and 49 controls, the authors measured acoustic startle responses to 96-dB startle pulses preceded 120, 240 (for PPI), 2,000, and 4,500 (for PPF) ms by a 68-dB prepulse noise. Geometric figures signaled that prepulses were to be ignored or attended to (automatic vs. controlled attention). ADHD patients exhibited deficits in prepulse modulation, but these reflected an interaction of controlled attention and time of information processing. Normal PPI and PPF occurred under all conditions except for controlled attentional modulation of PPI. Attention deficits in ADHD patients may reflect not general derangements in information processing or ability to attend but, rather, selective disturbances of controlled attention during early information processing., (Copyright 2010 APA, all rights reserved)

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Searching for a peripheral biological marker for schizophrenia, we previously reported on elevated mitochondrial complex I 75-kDa subunit mRNA-blood concentrations in early onset schizophrenia (EOS). The aim of this study was to further evaluate the utility of this gene as a potential marker for schizophrenia. Both-schizophrenia and autism-are suggested to be neuronal maldevelopmental disorders with reports of mitochondrial dysfunction and increased oxidative stress. Therefore we have investigated the expression levels of mitochondrial complex I 75-kDa subunit mRNA in whole blood of children with autistic spectrum disorder (ASD) and a group of adolescent acute first-episode EOS patients in comparison to matched controls. We have found that compared to the respective controls only the group of EOS patients-and not the ASD group-showed a significantly altered expression of the complex I 75-kDa subunit mRNA. Although further studies are necessary to test for the specificity of this marker, our findings point to the potential use of the mitochondrial complex I as a biomarker for schizophrenia.

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4-5% in children and 1-4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3'-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3'-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Background & Aims: Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides, and often remains undiagnosed. It is a complex genetic disorder, although 95% of the patients carry the risk heterodimer human leukocyte antigen (HLA)-DQ2. Genome-wide association studies on CD have identified 9 non-HLA loci that also contribute to CD risk, most of which are shared with other immune-related diseases. Our aim is to predict the genetic risk for CD using HLA and non-HLA risk alleles., Methods: We selected 10 independent polymorphisms in 2,308 cases and 4,585 controls from Dutch, UK, and Irish populations and categorized the individuals into 3 risk groups, based on their HLA-DQ2 genotype. We used the summed number of non-HLA risk alleles per individual to analyze their cumulative effect on CD risk, adjusting for gender and population group in logistic regression analysis. We validated our findings in 436 Italian cases and 532 controls., Results: CD cases carried more non-HLA risk alleles than controls: individuals carrying > or = 13 risk alleles had a higher CD risk (odds ratio, 6.2; 95% confidence interval, 4.1-9.3) compared with those carrying 0-5 risk alleles. Combining HLA and non-HLA risk genotypes in one model increases sensitivity by 6.2% compared with using only HLA for identification of high-risk individuals with slight decrease in specificity., Conclusions: We can use non-HLA risk factors for CD to improve identification of high-risk individuals. Our risk model is a first step toward better diagnosis and prognosis in high-risk families and population-based screening.

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts., Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p<1 x 10(-04) and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls)., Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3 x 10(-08), and rs842647 p = 5.2 x 10(-07)). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression., Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain approximately 40% of the heritability of coeliac disease.

The OTOF gene encoding otoferlin is associated with auditory neuropathy (AN), a type of non-syndromic deafness. We investigated the contribution of OTOF mutations to AN and to non-syndromic recessive deafness in Brazil. A test for the Q829X mutation was carried out on a sample of 342 unrelated individuals with non-syndromic hearing loss, but none presented this mutation. We selected 48 cases suggestive of autosomal recessive inheritance, plus four familial and seven isolated cases of AN, for genotyping of five microsatellite markers linked to the OTOF gene. The haplotype analysis showed compatibility with linkage in 11 families (including the four families with AN). Samples of the 11 probands from these families and from seven isolated cases of AN were selected for an exon-by-exon screening for mutations in the OTOF gene. Ten different pathogenic variants were detected, among which six are novel. Among the 52 pedigrees with autosomal recessive inheritance (including four familial cases of AN), mutations were identified in 4 (7.7%). Among the 11 probands with AN, seven had at least one pathogenic mutation in the OTOF gene. Mutations in the OTOF gene are frequent causes of AN in Brazil and our results confirm that they are spread worldwide.

Background: Emotional-motivational dysfunctions likely contribute to attention-deficit/hyperactivity disorder (ADHD), especially to hyperactive and impulsive symptoms. This study examined the affective modulation of the startle reflex in a large sample of ADHD patients. The aim was to compare subtypes of ADHD., Methods: One hundred ninety-seven unmedicated adult ADHD patients (127 combined type [ADHD-C]; 50 inattentive type [ADHD-I]; 20 hyperactive-impulsive type [ADHD-HI]) and 128 healthy control subjects were examined. The affect-modulated startle response as well as valence and arousal ratings were assessed for pleasant, neutral, and unpleasant picture stimuli., Results: Control subjects exhibited startle response attenuation and potentiation by pleasant and unpleasant pictures, respectively. In ADHD-HI, startle response was not attenuated by pleasant and not potentiated by unpleasant stimuli. In ADHD-C, startle response was not attenuated by pleasant pictures, and ADHD-I responded similar to control subjects but startle response was attenuated to a lesser degree by pleasant stimuli. The ADHD-HI group rated all pictures as more positive, and male ADHD-HI rated unpleasant stimuli as less arousing., Conclusions: This is the first study to assess the affect-modulated startle response in ADHD. It confirms emotional dysfunctions in these patients; all subtypes showed more or less diminished emotional reactions to pleasant stimuli. The hyperactive-impulsive type was also marked by blunted reactions to unpleasant stimuli. Results suggest that response patterns to emotional cues or reward may help to differentiate ADHD subtypes. Blunted emotional reactivity is especially pronounced in ADHD patients with symptoms of hyperactivity and impulsivity (ADHD-C, ADHD-HI).

Human leukocyte antigen (HLA) genes, located on chromosome 6p21.3, have a crucial role in susceptibility to various autoimmune and inflammatory diseases, such as celiac disease and type 1 diabetes. Certain HLA heterodimers, namely DQ2 (encoded by the DQA1*05 and DQB1*02 alleles) and DQ8 (DQA1*03 and DQB1*0302), are necessary for the development of celiac disease. Traditional genotyping of HLA genes is laborious, time-consuming, and expensive. A novel HLA-genotyping method, using six HLA-tagging single-nucleotide polymorphisms (SNPs) and suitable for high-throughput approaches, was described recently. Our aim was to validate this method in the Finnish, Hungarian, and Italian populations. The six previously reported HLA-tagging SNPs were genotyped in patients with celiac disease and in healthy individuals from Finland, Hungary, and two distinct regions of Italy. The potential of this method was evaluated in analyzing how well the tag SNP results correlate with the HLA genotypes previously determined using traditional HLA-typing methods. Using the tagging SNP method, it is possible to determine the celiac disease risk haplotypes accurately in Finnish, Hungarian, and Italian populations, with specificity and sensitivity ranging from 95% to 100%. In addition, it predicts homozygosity and heterozygosity for a risk haplotype, allowing studies on genotypic risk effects. The method is transferable between populations and therefore suited for large-scale research studies and screening of celiac disease among high-risk individuals or at the population level.

Attention-Deficit/Hyperactivity Disorder (ADHD) in adults is associated with deficits in executive functions such as verbal fluency. Functional near-infrared spectroscopy offers the possibility to measure brain activity during verbal fluency in psychiatric patients due to low susceptibility to movements artefacts. Fourteen patients with mainly combined ADHD subtype and 14 healthy controls matched for age, gender, handedness, education level, and intelligence showed equal performance in phonological verbal fluency and higher performance in semantical verbal fluency in comparison to the controls. On the level of brain function indicated by concentration changes of oxygenated and deoxygenated haemoglobin, both groups showed inferior frontal brain activity during both tasks. ADHD patients had a lower magnitude of oxygenation and a significant negative correlation of brain activity with performance, i.e. higher brain activity was associated with lower performance. These results might be interpreted as a lack of disease related deficits, as an economical recruitment of cognitive resources, or - more likely - as an expression of a benefit in the patient group. High verbal competence in our samples could contribute to these findings. One speculative and post hoc explanation aims at the clinically well-known phenomenon of hyperfocusing in patients with ADHD.

A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing approximately 500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

Background: The HLA genes, located in the MHC region on chromosome 6p21.3, play an important role in many autoimmune disorders, such as celiac disease (CD), type 1 diabetes (T1D), rheumatoid arthritis, multiple sclerosis, psoriasis and others. Known HLA variants that confer risk to CD, for example, include DQA1*05/DQB1*02 (DQ2.5) and DQA1*03/DQB1*0302 (DQ8). To diagnose the majority of CD patients and to study disease susceptibility and progression, typing these strongly associated HLA risk factors is of utmost importance. However, current genotyping methods for HLA risk factors involve many reactions, and are complicated and expensive. We sought a simple experimental approach using tagging SNPs that predict the CD-associated HLA risk factors., Methodology: Our tagging approach exploits linkage disequilibrium between single nucleotide polymorphism (SNPs) and the CD-associated HLA risk factors DQ2.5 and DQ8 that indicate direct risk, and DQA1*0201/DQB1*0202 (DQ2.2) and DQA1*0505/DQB1*0301 (DQ7) that attribute to the risk of DQ2.5 to CD. To evaluate the predictive power of this approach, we performed an empirical comparison of the predicted DQ types, based on these six tag SNPs, with those executed with current validated laboratory typing methods of the HLA-DQA1 and -DQB1 genes in three large cohorts. The results were validated in three European celiac populations., Conclusion: Using this method, only six SNPs were needed to predict the risk types carried by >95% of CD patients. We determined that for this tagging approach the sensitivity was >0.991, specificity >0.996 and the predictive value >0.948. Our results show that this tag SNP method is very accurate and provides an excellent basis for population screening for CD. This method is broadly applicable in European populations.

Previous genome-wide linkage studies applied the affected sib-pair design; one investigated extended pedigrees of a genetic isolate. Here, results of a genome-wide high-density linkage scan of attention-deficit/hyperactivity disorder (ADHD) using an array-based genotyping of approximately 50 K single nucleotide polymorphism (SNPs) markers are presented. We investigated eight extended pedigrees of German origin that were non-related, not part of a genetic isolate and ascertained on the basis of clinical referral. Two parametric analyses maximizing LOD scores (MOD) and a non-parametric analysis for both a broad and a narrow phenotype approach were conducted. Novel linkage loci across all families were detected at 2q35, 5q13.1, 6q22-23 and 14q12, within individual families at 18q11.2-12.3. Further linkage regions at 7q21.11, 9q22 and 16q24.1 in all families, and at 1q25.1, 1q25.3, 9q31.1-33.1, 9q33, 12p13.33, 15q11.2-13.3 and 16p12.3-12.2 in individual families replicate previous findings. High-resolution linkage mapping points to several novel candidate genes characterized by dense expression in the brain and potential impact on disorder-relevant synaptic transmission. Our study provides further evidence for common gene effects throughout different populations despite the complex multifactorial etiology of ADHD.

Background: Intraperitoneal chemotherapy has been recommended as a treatment option for ovarian cancer with peritoneal dissemination. Although its treatment duration is significantly shorter, intraoperative hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) has several advantages over simple intraperitoneal instillation chemotherapy. While platinum compounds have usually been used, only a few have administered paclitaxel during HIPEC. Its large molecular weight suggests a much more favorable pharmacokinetic profile than that of platinum compounds. The pharmacokinetics of paclitaxel during and after HIPEC have not been studied before., Methods: Thirteen women, mainly with ovarian cancer, underwent cytoreductive surgery and HIPEC with 175 mg/m(2) paclitaxel for 2 h. Morbidity was noted. Peritoneal fluid samples and blood samples were harvested during and until 5 days after HIPEC for pharmacokinetic study in ten patients., Results: No treatment-related mortality was noted. Overall morbidity was 38% (two wound infections, one deep venous thrombosis, two grade 1 thrombopenia, one grade 2 neutropenia, and one grade 3 pancytopenia). Mean maximal intraperitoneal paclitaxel concentration was 101 mg/L, which was an average of 1178 times higher than the peak plasma levels. The peritoneal fluid versus plasma AUC ratio was 1462 for the 2-h HIPEC duration and 366 for the total 5-day study period. Cytotoxic drug concentrations were detected in peritoneal fluid for a mean period of 2.7 days, despite drainage of the drug solution after 2 h of treatment., Conclusions: HIPEC with paclitaxel following cytoreductive surgery is feasible, relatively safe, and associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Larger studies with a more homogenous patient cohort and adequate follow-up should be performed to demonstrate its efficacy.

Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

Background: Celiac disease (CD) is a complex genetic disorder of the small intestine resulting from aberrant cellular responses to gluten peptides. It may affect as much as 1% of the Western population and the only treatment is a lifelong gluten-free diet. Allelic variants of the HLA-DQ locus, coding for the HLA-DQ2 and HLA-DQ8 molecules, contribute to ∼ 40% of CD etiology, whereas other genes, such as MYO9B, CTLA4, IL2, IL21, PARD3 and MAGI2, have only a modest effect. Most of these genes have shown varied association among different populations and an overlap with other autoimmune or inflammatory disorders, indicating that such disorders may share common pathways., Objectives: In this review, a molecular approach into diagnostics of celiac disease is shown., Conclusions: Genome-wide association studies will allow more genes to be identified, and knowing how risk variants combine will help to predict better the risk for the individual. HLA typing can already be used to identify high-risk individuals.

Nonsyndromic autosomal recessive deafness accounts for 80% of hereditary deafness. To date, 52 loci responsible for autosomal recessive deafness have been mapped and 24 genes identified. Here, we report a large inbred Brazilian pedigree with 26 subjects affected by prelingual deafness. Given the extensive consanguinity found in this pedigree, the most probable pattern of inheritance is autosomal recessive. However, our linkage and mutational analysis revealed, instead of an expected homozygous mutation in a single gene, two different mutant alleles and a possible third undetected mutant allele in the MYO15A gene (DFNB3 locus), as well as evidence for other causes for deafness in the same pedigree. Among the 26 affected subjects, 15 were homozygous for the novel c.10573delA mutation in the MYO15A gene, 5 were compound heterozygous for the mutation c.10573delA and the novel deletion c.9957&#95;9960delTGAC and one inherited only a single c.10573delA mutant allele, while the other one could not be identified. Given the extensive consanguinity of the pedigree, there might be at least one more deafness locus segregating to explain the condition in some of the subjects whose deafness is not clearly associated with MYO15A mutations, although overlooked environmental causes could not be ruled out. Our findings illustrate a high level of etiological heterogeneity for deafness in the family and highlight some of the pitfalls of genetic analysis of large genes in extended pedigrees, when homozygosity for a single mutant allele is expected.

Purpose: To determine the application and clinical effectiveness of ePTFE/FEP-covered metallic stents for palliation of malignant biliary disease, and to evaluate the efficiency of stent coverage in preventing tumor ingrowth., Methods: During a 3-year period, 36 patients with malignant obstructive jaundice were treated with ePTFE/FEP-covered stents, with or without proximal side holes. The stricture was located in the lower common bile duct (CBD) in 18 cases, the upper CBD in 9, the lower common hepatic duct (CHD) in 6, and the upper CHD in 3 patients., Results: Thirty-seven covered stents were percutaneously implanted. The technical success rate was 97%. Reintervention was required in 6 cases. The 30-day mortality rate was 40%, not procedure-related. Mean survival was 128 days. Primary patency rates were 100%, 55.5%, and 25% at 3, 6, and 12 months, respectively, while the assisted patency rate was 100% at 12 months. Stents without side holes had higher primary patency rates compared with those with side holes, where occlusion was always due to tumor ingrowth. Tumor ingrowth did not occur in the completely covered stents. No stent dysfunction due to sludge incrustation was found. Complications were 1 case of arterial laceration that occurred during percutaneous transhepatic cholangiography, and a subcapsular hematoma and 1 case of bile peritonitis, that both occurred during primary stenting. No complications followed the secondary stenting technique., Conclusion: ePTFE/FEP-covered metallic stents are safe and effective for palliation of malignant biliary disease. The presence of the ePTFE/FEP coating is likely to prevent from tumor ingrowth.