Understanding and breaking the intergenerational cycle of abuse in families enrolled in routine mental health services: study protocol for a randomized controlled trial and two non-interventional trials investigating mechanisms of change within the UBICA II consortium.

BACKGROUND: Parents' mental illness (MI) and parental history of early life maltreatment (ELM) are known to be significant risk factors for poor parenting while poor parenting is a crucial mediator of the intergenerational continuity of child maltreatment. Hence, maltreatment prevention programs for families with an MI parent, which pay particular attention to experiences of ELM in the parent, are urgently needed. Parental mentalizing was previously found to mediate successful parenting. Interventions aimed at improving the parental mentalizing capacity reduced maltreatment risk in parents. The aim of the present study is to investigate the effectiveness of a mentalization-based parenting-counseling in acutely mentally ill parents currently treated at a psychiatric hospital. METHODS: Mentalization-based parenting-counseling (MB-PC) vs. enhanced standard clinical care (SCC+) will be administered in a cluster-randomized-controlled trial (RCT). Patients treated at psychiatric hospitals with children between 1.5 and 15 years will be included in the trial. MB-PC will be administered as a 12-h combined individual and group program enriched by social counseling (over a course of 5 weeks) as add-on to standard clinical care, while the control condition will be standard clinical care plus a 90-min psychoeducation workshop on positive parenting. Primary efficacy endpoint is self-reported parenting practices at follow-up. Embedded within the RCT will be two sub-studies investigating social cognition and dyadic synchrony as biobehavioral mechanisms of change. DISCUSSION: The main goal of the present study is to investigate ways to break the intergenerational continuity of maltreatment by assessing the benefits of a prevention program which aims at improving parenting in vulnerable mothers and fathers. MB-PC is a short, low-cost intervention which can be delivered by nurses and social workers and is applicable to MI patients with children with a broad range of diagnoses. If it is shown to be effective, it can be directly implemented into standard psychiatric hospital care thereby providing help to prevent child maltreatment. TRIAL REGISTRATION: German Clinical Trials Register DRKS00017398 . Registered on 5 July 2019.

A mechanism-based group-psychotherapy approach to aggressive behaviour in borderline personality disorder: findings from a cluster-randomised controlled trial.

BACKGROUND: Aggressive behaviour is a prevalent and harmful phenomenon in patients with borderline personality disorder (BPD). However, no short-term, low-cost programme exists that specifically focuses on aggression. AIMS: Attuning therapy modules to pathogenetic mechanisms that underlie reactive aggression in BPD, we composed a 6 week mechanism-based anti-aggression psychotherapy (MAAP) approach for the group setting, which we tested against a non-specific supportive psychotherapy (NSSP). METHOD: A cluster-randomised two-arm parallel-group phase II trial of N = 59 patients with BPD and overt aggressive behaviour was performed (German Registry for Clinical Trials, DRKS00009445). The primary outcome was the externally directed overt aggression score of the Modified Overt Aggression Scale (M-OAS) post-treatment (adjusted for pre-treatment overt aggression). Secondary outcomes were M-OAS irritability, M-OAS response rate and ecological momentary assessment of anger post-treatment and at 6 month follow-up, as well as M-OAS overt aggression score at follow-up. RESULTS: Although no significant difference in M-OAS overt aggression between treatments was found post-treatment (adjusted difference in mean 3.49 (95% CI -5.32 to 12.31, P = 0.22), the MAAP group showed a clinically relevant decrease in aggressive behaviour of 65% on average (versus 33% in the NSSP group), with particularly strong improvement among those with the highest baseline aggression. Most notably, significant differences in reduction in overt aggression between MAAP and NSSP were found at follow-up. CONCLUSIONS: Patients with BPD and aggressive behaviour benefited from a short group psychotherapy, with improvements particularly visible at 6 month follow-up. Further studies are required to show whether these effects are specific to MAAP.

Longitudinal Volume Quantification of Deep Medullary Veins in Patients with Cerebral Venous Sinus Thrombosis : Venous Volume Assessment in Cerebral Venous Sinus Thrombosis Using SWI.

PURPOSE: Susceptibility-weighted imaging (SWI) visualizes small cerebral veins with high sensitivity and could, thus, enable quantification of hemodynamics of deep medullary veins. We aimed to evaluate volume changes of deep medullary veins in patients with acute cerebral venous sinus thrombosis (CVST) over time in comparison to healthy controls. METHODS: All magnetic resonance imaging (MRI) experiments were executed at 3 T using a 32-channel head coil. Based on SWI and semiautomatic postprocessing (statistical parametric mapping [SPM8] and ANTs), the volume of deep medullary veins was quantified in 14 patients with acute CVST at baseline and the 6­month follow-up, as well as in 13 healthy controls undergoing repeated MRI examination with an interscan interval of at least 1 month. RESULTS: Deep medullary venous volume change over time was significantly different between healthy controls and patient groups (p < 0.001). Patients with superior sagittal sinus thrombosis (SSST) showed a significant decline from baseline to follow-up measurements (9.8 ± 4.9 ml versus 7.5 ± 4.2 ml; p = 0.02), whereas in patients with transverse sinus thrombosis (TST) and healthy controls no significant volume changes were observable. CONCLUSIONS: Venous volume quantification was feasible and reproducible both in healthy volunteers and in patients. The decrease of venous volume in patients over time represents improvement of venous drainage, reduction of congestion, and normalization of microcirculation due to treatment. Thus, quantification of venous microcirculation could be valuable for estimation of prognosis and guidance of CVST therapy in the future.

Reliability of cerebral vein volume quantification based on susceptibility-weighted imaging.

INTRODUCTION: Susceptibility-weighted imaging (SWI) visualizes even small cerebral veins and might, therefore, be valuable in monitoring neurological diseases affecting cerebral veins. Since it is generally difficult to evaluate individual results of quantitative MRI measurements, an automatic approach would be highly appreciated to assist the diagnostic process. The aim of this study was to evaluate the rescan and reanalysis reliability using an automatic venous volumetric approach based on SWI in healthy controls. METHODS: SWI was performed in ten healthy controls undergoing MRI examinations using a 32-channel head coil at 3 T five times on five different days. To test for rescan and reanalysis variability, the deep cerebral vein volume was quantified using ANTs and SPM8. RESULTS: Total volumes of cerebral deep veins measured during five MRI scans in ten individuals (n = 50 scans) showed intra-individual volume changes ranging from 0.07 to 1.03 ml (mean variability = 10.2 %). Automatic reanalyses revealed exactly the same results in all scans. CONCLUSION: Automatic SWI-based cerebral vein volumetry shows acceptable rescan-and excellent reanalyses-reliability in healthy volunteers. Therefore, this approach might be beneficial in intra-individual follow-up studies of neurological diseases affecting the cerebral venous system.

Facing the Time Window in Acute Ischemic Stroke: The Infarct Core.

BACKGROUND: Increasing numbers needed to treat within the first hours after ischemic stroke onset indicate a strong time dependency of the viability of brain tissue. However, this time dependency is not reflected in recent randomized controlled trials of endovascular stroke treatment. This study evaluates whether and to which extent a time dependency exists in patients with embolic carotid T or M1 occlusions within the first 6 h of stroke onset. METHODS: Patient data were retrieved from the Freiburg stroke data bank. Time from onset to acquisition of the diffusion weighted images (DWIs) varied between 49 and 357 min. Ischemic lesions were semiautomatically segmented on apparent diffusion coefficient maps with a threshold of 600 × 10 (- 6) mm(2)/s. Occlusion location and thrombus length were determined with magnetic resonance angiography, T2*, and more recently susceptibility weighted image (SWI) sequences. A hyperintense vessel sign in FLAIR images as a possible surrogate for collaterals was also identified. RESULTS: A total of 155 patients with occlusions of the carotid T (n = 26), proximal M1 segment (n = 44), and distal M1 segment (n = 85) of the middle cerebral artery between 2011 and 2015 were included. Infarct volumes varied from 0.3 to 180.2 mL. Infarct size did not correlate with stroke onset to DWI times. Infarct volumes also did not associate with different locations of vessel occlusion, thrombus length, presence of the hyperintense vessel sign and initial infarct growth. CONCLUSION: We found no significant time dependency of the viability of brain tissue with embolic carotid T or M1 occlusions between 1 and 6 h after stroke onset. The early infarction volume is thus probably determined in the hyperacute phase by the quality of leptomeningeal collaterals and comparatively stable in this time period.

Screening for anorexia nervosa via measurement of serum leptin levels.

Due to their sub-normally low fat mass, leptin levels in patients with acute anorexia nervosa (AN) are well below reference levels for age and sex-matched controls. This hypoleptinemia entails endocrinological and behavioral characteristics observed in AN patients during starvation. We aimed to study the appropriateness of hypoleptinemia as a diagnostic marker for AN by assessing sensitivity, specificity and likelihood ratios for different referral serum leptin levels for predicting anorexia nervosa and healthy leanness. For prediction, we additionally generated a score based on a multivariate logistic model including body mass index (BMI; kg/m²) and leptin level. For this purpose, we measured leptin levels in 74 female patients with acute AN upon admission for inpatient or outpatient treatment. Adolescent and adult patients were recruited according to DSM-IV criteria from two multi-center studies. Additionally, leptin levels were measured in 65 female healthy, lean students. Mean serum leptin level was significantly decreased in patients with AN compared to underweight controls (0.87 ± 0.90 vs. 6.43 ± 3.55 µg/L, p < 0.001). Leptin predicted AN independently of BMI; we confirmed a cutoff value in the range of 2 µg/L as having both high specificity and sensitivity. Hypoleptinemia represents a state marker of acute AN and is useful for a laboratory-based diagnostic screening.

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domain-containing protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 α subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a ∼3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P=0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

Exploring the genetic link between RLS and ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 (chi2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A-A-A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.

Allelic variants of SNAP25 in a family-based sample of ADHD.

Altered neurotransmission has been suggested to be a crucial factor in the pathophysiology of attention-deficit/hyperactivity disorder ADHD. Subsequently genes encoding for synaptic proteins have been investigated in candidate gene studies. These proteins mediate the release of neurotransmitters into the synaptic cleft in the process of signal transduction by forming a transient complex, enabling the junction of vesicle and synaptic membrane. One of the core proteins of this complex is the synaptosomal-associated protein 25 (SNAP25). It is one of the most validated candidate genes in ADHD according to meta-analyses. However, differing results were observed in previous studies, some of which were not able to observe association with ADHD. In this study we aimed to investigate association of genetic variants of SNAP25 located in the putative promoter region of SNAP25 and a SNP in intron 8, previously reported to associated with ADHD. A family based design was applied to detect preferential transmission of genetic variants. In our German ADHD sample no preferential transmission of either variant could be observed. Further investigation considering sub-sample analysis regarding response to D-amphetamine could enlight the role of SNAP25 in ADHD.

Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12.

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.

Association and linkage of allelic variants of the dopamine transporter gene in ADHD.

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.

No evidence for preferential transmission of common valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor gene (BDNF) in ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample.

Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample.

Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.

Transcutaneous contrast enhanced sonography of the chest for evaluation of pleural based pulmonary lesions: experience in 137 patients.

PURPOSE: Transcutaneous ultrasound enables visualization of pleural based lesions but with a poor correlation to specific pathology. Ultrasound contrast agents in conjunction with contrast specific imaging techniques are increasingly accepted in clinical use. Up to date there are no data about the use of contrast enhanced sonography (CES) in a large series of pleural based pulmonary lesions. MATERIALS AND METHODS: From August 2004 to August 2005, 137 consecutive patients with pleural based pulmonary lesions on B-mode sonography were studied by CES using a transcapillary second-generation contrast agent (SonoVue(R)). The following CES parameters were retrospectively evaluated. Time to enhancement (TE) of contrast agent after i. v. application was determined and classified as short TE (< = 6 sec) vs. delayed TE (> 6 sec). Extent of enhancement (EE) was evaluated during the arterial phase (2 - 30 sec) and the parenchymal phase (1 - 5 minutes) by using the normal splenic tissue as an in vivo reference, and classified in reduced EE (anechoic/hypoechoic) vs. marked EE (isoechoic/hyperechoic) during both phases. Homogeneity of enhancement (HE) was classified as homogeneous vs. inhomogeneous. 60 patients had histologically confirmed malignant lesions due to central lung cancer (n = 31), and peripheral malignant lesions (n = 29). 77 patients had benign pleural based lesions including pneumonia (n = 32), pulmonary embolism (n = 20), compression atelectasis (17), and other benign pleural based lesions (n = 8). RESULTS: Malignant and benign lesions did not vary significantly regarding TE, EE, and HE. However, there were highly significant differences in the ratio of short vs. delayed TE and reduced vs. marked EE between the six disease groups. Characteristic patterns were short TE with marked EE in all compression atelectasis cases and in 62 % of patients with pneumonia. Delayed TE and reduced EE was seen in all patients with pulmonary embolism and in 62 % of patients with peripheral malignant lesions. Central lung cancer and benign nodules did not present with such specific patterns. No significant differences in HE were seen between subgroups. CONCLUSION: Pulmonary lesions are characterized by different CES-patterns of arterial supply as evidenced by TE and EE which depends on underlying causes, but CES does not allow to distinguish benign from malignant pleural based lesions in general.

Platelets do not adsorb HLA class I molecules during storage of pooled platelet concentrates.

The origin of HLA class I molecules on platelets is still under discussion. Adsorption of HLA molecules on platelets using specific experimental conditions has been described. The study presented investigates whether there is a significant elution and adsorption of HLA class I molecules on platelets during storage of pooled random platelet concentrates (PRPC) under routine conditions. Platelet concentrates (PCs) from whole blood were prepared from HLA-A2-positive and HLA-A2-negative donors, pooled and stored under routine conditions. In addition, platelets from HLA-A2-negative donors were pelleted and resuspended in cell-free plasma from HLA-A2-positive donors. HLA-A2-positive PCs (positive control), HLA-A2-negative PCs (negative control) and HLA-A2-negative platelets in plasma from HLA-A2-negative donors were stored simultaneously. Binding of FITC-conjugated monoclonal murine antihuman HLA-A2 antibodies (anti-HLA-A2-mab) was measured during 5-day storage by flow cytometry. An increased binding of anti-HLA-A2-mab during storage was found on HLA-A2-negative platelets (P < 0.005) independently whether they were incubated with cell-free plasma or platelets from HLA-A2-positive donors or autologous HLA-A2-negative cell-free plasma. However, non-specific binding of IgG controls increased equally, whereas anti-HLA-A2-mab binding to platelets from HLA-A2-positive donors did not decrease during storage. This study suggests that there is no significant elution and adsorption of HLA class I antigens of platelets in pooled PCs during storage under the usual conditions for platelet storage. Increased anti-HLA-A2-mab signal was due to non-specific binding. Therefore, HLA class I compatible platelets should maintain their compatibility for an immunized patient when stored in a pool with HLA incompatible platelets and shortened survival after transfusion should not be expected.

A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs.

Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.

Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P=0.049; rs11178997, P=0.034), but not for the third SNP in intron 2 (rs4565946, P=0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P=0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes.

TNF-alpha-, TNF-beta-, IL-6-, and IL-10-promoter polymorphisms in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major health problem. The disease is driven by abnormal inflammatory reactions in response to inhaled particles and fumes. Therefore, inflammatory mediators are postulated to be of distinct importance. In the present case-control study, we investigated interleukin (IL)-promoter polymorphisms known to correlate with altered transcription levels of their gene products in patients with COPD. We analyzed tumor necrosis factor-alpha (TNF-alpha)-308, TNF-beta-intron1-252, IL-6-174, IL-10-819, and IL-10-1082 polymorphisms in 469 individuals using restriction fragment length polymorphism-based converted polymerase chain reaction. The study population consisted of 113 patients with COPD based on chronic bronchitis, divided into subgroups by severity (I degrees -III degrees ), 113 matched hospitalized individuals suffering from severe coronary heart disease without pulmonary disease (age-, sex-, and smoking-matched control group), and 243 healthy individuals (population control group). The matched analysis showed no significant differences in genotype distribution of all tested polymorphisms between the matched controls and the COPD patients. However, comparison with the population controls revealed significant differences in IL-10-1082 A/G genotype frequencies (P = 0.0247 for the whole COPD group, P = 0.009 for smokers only), with the genotypes carrying the G allele more common in the COPD cases [odds ratio (OR) = 1.66, 95% confidence interval (CI) 1.01-2.75; P = 0.046]. Interestingly, this shift toward more G alleles was even more pronounced in the matched control group (OR = 2.55, 95% CI 1.47-4.41; P = 0.0007), suggesting both presented groups share corresponding underlying mechanisms. The IL-10-1082_G allele is known to correlate with altered IL-10 levels. Therefore, it might be associated with altered or abnormal inflammatory response, a mechanism that could be postulated to be important in both chronic bronchitis and coronary heart disease.

Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention-deficit/hyperactivity disorder.

Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Molecular genetic aspects of attention-deficit/hyperactivity disorder.

Two genome wide scans, one of which was subsequently extended, have led to the identification of different chromosomal regions assumed to harbour genes underlying attention-deficit/hyperactivity disorder (ADHD). Some of these regions were also identified in patients with autism and/or dyslexia. The only region for which both studies detected a LOD score >1 was on chr 5p13 which is in the vicinity of the location of the candidate gene DAT1. The candidate gene approach has revealed the most robust and replicated findings for DRD4, DRD5, and DAT1 polymorphisms. Meanwhile interesting endophenotype studies have also been conducted suggesting a genetic basis for different diagnostic and therapeutic criteria. Animal studies for ADHD have investigated especially hyperactivity and have focused mainly on knockout and QTL designs. In knockout mice models the most promising results were obtained for genes of the dopaminergic pathway. QTL results in rodents suggest multiple loci underlying different forms of natural and induced hyperactivity. The molecular results mentioned above are presented and discussed in detail, thus providing both clinicians and geneticists with an overview of the current research status of this important child and adolescent psychiatric disorder.