Evidence for an influence of TCF7L2 polymorphism rs7903146 on insulin resistance and sensitivity indices in overweight children and adolescents during a lifestyle intervention.

OBJECTIVE: The T allele of the single-nucleotide polymorphism rs7903146 in TCF7L2 (transcription factor 7 like 2 gene) is associated with type 2 diabetes mellitus. The aim of this study was to analyze whether there is an allele-dosage effect on changes of insulin resistance and sensitivity indices in overweight children participating in a lifestyle intervention. METHODS: We genotyped rs7903146 in 236 overweight children (mean age 10.7 years, mean body mass index (BMI) 28.1 kg/m2) completing a 1-year lifestyle intervention. Degree of overweight as BMI-SDS, homeostasis model assessment for insulin resistance (HOMA-IR) and the insulin sensitivity index QUICKI were measured before and after intervention. RESULTS: Lifestyle intervention resulted in an overweight reduction of -0.29+/-0.02 BMI-SDS. HOMA-IR (-0.63+/-0.22) and QUICKI (+0.008+/-0.003) indices improved significantly (P<0.05) in the course of the intervention in the 155 children with a decrease of BMI-SDS. There was an additive negative effect of T allele on changes of HOMA-IR (P=0.041) and QUICKI (P=0.001) in linear regression analyses adjusted to changes of weight status, age, gender and pubertal stage. CONCLUSION: Overweight children showed a negative dosage-allele effect per T allele at single-nucleotide polymorphism rs7903146 in TCF7L2 concerning an improvement of insulin resistance and sensitivity after overweight reduction in a lifestyle intervention. This finding further suggests that this polymorphism might be involved in glucose metabolism.

Dispositional mindfulness is predicted by structural development of the insula during late adolescence.

Adolescence is a critical period of development, in which the increasing social and cognitive demands of independence need to be met by enhanced self-regulatory abilities. The cultivation of mindfulness has been associated with improved self-regulation in adult populations, and it is theorized that one neurodevelopmental mechanism that supports this capacity is the development of the prefrontal cortex. The current study examined the neurodevelopmental mechanisms associated with dispositional mindfulness in adolescence. Using a longitudinal within-persons design, 82 participants underwent structural magnetic resonance imaging (MRI) assessments at approximately ages 16 and 19, and also completed self-reported measurements of mindfulness at age 19. It was hypothesized that adolescents who demonstrated greater thinning of frontal cortical regions between the age of 16 and 19 would exhibit higher dispositional mindfulness levels at age 19. Results indicated that, contrary to predictions, adolescents with higher levels of mindfulness demonstrated less thinning in the left anterior insula. By contrast, higher IQ was associated with greater thinning of the right caudal middle frontal and right superior frontal regions. The involvement of insula development in mindfulness is consistent with a direct role for this structure in managing self-regulation, and in doing so concords with recent models of self-referential interoceptive awareness.

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.

Perspectives: molecular genetic research in human obesity.

Within the past decade the molecular basis of single forms of monogenic obesity has been elucidated. With the exception of functionally relevant mutations in the melanocortin-4 receptor gene, which occur in approximately 2-4% of extremely obese individuals, all other currently known monogenic forms are rare and additionally associated with distinct endocrinological abnormalities. A large number of association studies have been performed in 'normal' obesity. Whereas many associations have been reported, it is largely unclear which of these represent true positive findings. Over 20 genome scans pertaining to obesity and related phenotypes have been performed; specific chromosomal peak regions have been identified in different scans. We review the current status and discuss relevant issues related to phenotyping, association and linkage studies. We recommend that the procedure via which a consensus is reached as to what constitutes a true positive association finding requires formalization.

Effect of keratometer and axial length measurement errors on primary implant power calculations.

Analytical predictions of primary implant power using presumptive errors in keratometer and axial length measurements were performed using the modified Binkhorst, modified Colenbrander, Holladay, Hoffer, and SRK II equations. These predictions demonstrate that the contributions to primary implant power error resulting from inaccurate axial length and keratometer measurements are algebraically additive. In eyes with a normal axial length, the resulting implant power determination error can be larger than differences in implant power prediction among these five IOL equations. Calculations using measurement errors of 0.2 mm in axial length and 0.50 diopter (D) in corneal curvature predicted a worst case primary implant power error of +/- 1.17 D. These calculations were performed using an axial length and corneal curvature near the population mean. In contrast, implant equation variability was determined to be +/- 0.19 D by calculating the standard deviation of the five implant power formulas with the measurement errors set to zero. Implant power prediction errors were increased when a flat cornea was paired with an axial hyperopic or an axial myopic eye. These combinations maximize the implant power error resulting from both implant formula variation and inaccurate measurements. Primary implant power error prediction tables are presented for emmetropic, axial hyperopic, and axial myopic eyes, as a function of presumed errors in axial length and corneal curvature. These error predictions clearly show that inaccuracy in axial length measurements and keratometer readings can be first order determinants of postoperative spherical refractive error.

Trigger finger: the effect of partial release of the first annular pulley on triggering.

A prospective, randomized study was performed on 19 patients, in whom the proximal, middle, or distal third of the first annular pulley was divided to determine if a specific portion of the first annular pulley was responsible for the clinical triggering associated with restrictive flexor tenosynovitis. In all 19 patients, a partial resection of the first annular pulley resulted in continued clinical triggering with active digital flexion. At this point, a standard complete first annular pulley release was performed, with resolution of clinical triggering of the involved digit in all patients. We conclude that there is no "critical third" of the first annular pulley responsible for clinical digital triggering.

[Leopard-spot pattern in fluorescein angiography]. / Leopardenmuster in der Fluoreszenzangiographie.

The uveal effusion syndrome is a rare disease characterized by serous choroidal detachment. The pathogenesis of idiopathic uveal effusion syndrome has not yet been conclusively established. One hypothesis is an abnormality of diffusion of extravascular proteins in the choroid leading to decompensation of the pigment epithelium pumping capacity. Fluid then accumulates in the subretinal space leading to retinal detachment which results in loss of visual acuity. It typically affects males and hypermetropia is another risk factor. When looking at the fundus a circular serous detachment of the choroid and choroidal puckering is typical. The fluorescein angiography shows hyperfluorescence in the form of a leopard-spot pattern. Space-occupying lesions have to be excluded with the help of ultrasound or magnetic resonance tomography. The uveal effusion syndrome is a diagnosis by exclusion. Treatment varies because of the different hypotheses for the pathogenesis. An intraocular tamponade in combination with laser coagulation may for example be an effective treatment.

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.

Genetic aspects in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder among children and adolescents with high heritability. Molecular genetic findings support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. Genetic research comprises formal genetic studies, candidate gene studies, linkage analyses, and recently large-scale genome wide association studies, gene-environement interaction studies, and pharmacogenetics. This article comprehensively reviews the latest findings on the genetics of ADHD.

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.

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.

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.

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.

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.

[Recent developments in the diagnosis and therapy of primary varicose veins]. / Neuere Gesichtspunkte der Diagnostik und Therapie der primären Varikosis.

Crossectomy and a stripping operation, on the one hand, plus sclerosis therapy on the other are emphasized as complementary non-competing measures in the therapeutic treatment of varicosis of the great saphenous system. Differential therapeutic management of varicosis in the great saphenous system is elucidated by means of grading classification of the primary varicosis.

Telethermography in the diagnostics and management of malignant melanomas.

Telethermography is a harmless, noninvasive method of examining some patients for some conditions. There are more important differential criteria than thermography for the diagnosis of malignant melanomas, but in some cases the proof of a surrounding difference in temperature may make a contribution to the diagnosis of malignant melanoma, especially if it gives decisive information as to the otherwise clinically inapparent extent of the malignancy locally, and thus guides the surgeon to excise widely enough. Also, thermography of the whole body is complementary to established techniques of examination used in evaluation of patients with malignant melanomas. By making visible hypo- or hyperthermic areas, it helps to detect metastases and confirms or denies suspicious findings obtained by other methods of examination.

A simplified method of monocanalicular silicone intubation.

We present a simplified method of monocanalicular silicone intubation for the repair of single canaliculus lacerations. A monocanalicular loop of tubing running from the punctum, through the lacerated canaliculus, and out the cutdown site over the lacrimal sac, provides a secure silicone tube stent.

Ocular syphilis and neurosyphilis in a patient with human immunodeficiency virus infection.

A patient who presented with severely decreased bilateral vision was found to have syphilis and neurosyphilis that responded well to a 14-day course of penicillin and prednisone. The patient tested positive for HIV, which can alter the natural course of syphilis, often making the diagnosis and treatment difficult. Conventional therapy for syphilis may not be effective in patients with HIV. Any patient with syphilis who is in a high-risk group should be tested for HIV; conversely, any patient with HIV should be tested for syphilis if signs or suspicions exist.

Neuroendocrine alterations in uveitis patients.

Experimental models of autoimmune uveitis are consistently associated with pinealitis. To investigate the interaction between the neuroendocrine and immune systems in humans with uveitis, we measured serum levels of the predominant pineal hormone melatonin (MEL), prolactin (PRL) and interleukin-2 (IL-2). A total of 100 patients with different forms of uveitis and 30 age-matched, healthy blood donors were evaluated retrospectively. The day-time MEL was reduced significantly (P < or = 0.01) in patients with iritis and iridocyclitis, and highly significantly (P < or = 0.001) in patients with intermediate uveitis, chorioretinitis and panuveitis. In 38% of patients day-time MEL levels in plasma were below the limit of detection. PRL was significantly reduced (P < 0.01) in patients with intermediate uveitis. IL-2 was reduced to about 50% of control values in all groups of patients. The results suggest a possible neuroendocrine-immune interaction in uveitis patients.