Meta-analysis and systematic review of ADGRL3 (LPHN3) polymorphisms in ADHD susceptibility.

The gene encoding adhesion G protein-coupled receptor L3 (ADGRL3, also referred to as latrophilin 3 or LPHN3) has been associated with ADHD susceptibility in independent ADHD samples. We conducted a systematic review and a comprehensive meta-analysis to summarize the associations between the most studied ADGRL3 polymorphisms (rs6551665, rs1947274, rs1947275, and rs2345039) and both childhood and adulthood ADHD. Eight association studies (seven published and one unpublished) fulfilled criteria for inclusion in our meta-analysis. We also incorporated GWAS data for ADGRL3. In order to avoid overlapping samples, we started with summary statistics from GWAS samples and then added data from gene association studies. The results of our meta-analysis suggest an effect of ADGRL3 variants on ADHD susceptibility in children (n = 8724/14,644 cases/controls and 1893 families): rs6551665 A allele (Z score = -2.701; p = 0.0069); rs1947274 A allele (Z score = -2.033; p = 0.0421); rs1947275 T allele (Z score = 2.339; p = 0.0978); and rs2345039 C allele (Z score = 3.806; p = 0.0026). Heterogeneity was found in analyses for three SNPs (rs6551665, rs1947274, and rs2345039). In adults, results were not significant (n = 6532 cases/15,874 controls): rs6551665 A allele (Z score = 2.005; p = 0.0450); rs1947274 A allele (Z score = 2.179; p = 0.0293); rs1947275 T allele (Z score = -0.822; p = 0.4109); and rs2345039 C allele (Z score = -1.544; p = 0.1226). Heterogeneity was found just for rs6551665. In addition, funnel plots did not suggest publication biases. Consistent with ADGRL3's role in early neurodevelopment, our findings suggest that the gene is predominantly associated with childhood ADHD.

Evidence on methylphenidate in children and adolescents with ADHD is in fact of 'very low quality'.

Banaschewski and colleagues from the European Attention Deficit Hyperactivity Disorder (ADHD) guideline group make a number of critical comments regarding our systematic review on methylphenidate for children and adolescents with ADHD. In this article, we present our views, showing that our trial selection was not flawed and was undertaken with scientific justification. Similarly, our data collection and interpretation was systematic and correct. We have followed a sound methodology for assessing risk of bias and our conclusions are not misleading. We acknowledge that different researchers might make risk of bias judgments at higher or lower thresholds, but we have been consistent and transparent in applying our pre-defined and per reviewed protocol. Although we made minor errors, we demonstrate that the effects are negligible and not affecting our conclusions. We are happy to correct such errors and to engage in debate on methodological and ethical issues. In terms of clinical implications, we are advocating that clinicians, patients and their relatives should weight carefully risks and benefits of methylphenidate. Clinical experience seems to suggest that there are people who benefit from this medication. Our systematic review does, however, raise questions regarding the overall quality of the methylphenidate trials.

BDNF Val66Met polymorphism and peripheral protein levels in pediatric bipolar disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: Frontiers between pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD) are not well defined. Few studies have addressed potentially different neurobiological factors between the two disorders. Brain-derived neurotrophic factor (BDNF) has been increasingly recognized for its etiologic and prognostic role in adult bipolar disorder (BD) studies. This study aimed to examine the BDNF gene polymorphism and potential alterations in BDNF serum levels in the pediatric ADHD patients with or without comorbid BD illness. METHOD: We assessed the non-synonymous single-nucleotide polymorphism in the BDNF gene (rs6265/Val66Met) and its serum levels in children and adolescents with BD comorbid with ADHD (BD + ADHD) and ADHD alone. Children and adolescents were assessed for psychiatric diagnoses using the Kiddie-Sads-Present and Lifetime Version (K-SADS-PL). RESULTS: Using Analysis of covariance (ancova) we detected a significant group effect (patients with BD + ADHD had higher serum levels than those with ADHD - F80,3 = 8.73, P = 0.005). CONCLUSION: Although the Val66Met polymorphism at the BDNF gene does not seem to play a significant role in children and adolescents with BD or ADHD, BDNF serum levels deserve further attention in future research on neurobiological aspects of BD and ADHD.

Accuracy of ultrasonography to establish the diagnosis and aetiology of permanent primary congenital hypothyroidism.

OBJECTIVE: To compare ultrasonography and 99mTc thyroid scintigraphy for the aetiologic diagnosis of permanent congenital hypothyroidism (CH). STUDY DESIGN: Eighty-eight consecutive patients with CH were recruited at an endocrinology outpatient clinic and submitted to high-frequency ultrasonography and to 99mTc scintigraphy. RESULTS: Seventy-six patients were diagnosed with permanent CH and 12 with transitory CH. The agreement between ultrasound and scintigraphy was very high (kappa coefficient = 0.866; P < 0.001) for the entire group. In permanent CH patients, ultrasonography identified 67 cases of dysgenesis (absence of thyroid gland in the usual anatomical location in 66 and hemiagenesis in one), and this diagnosis was confirmed by scintigraphy (absence of functional thyroid tissue in 43 and ectopia in 24). In the other nine permanent CH patients, the thyroid was in the usual anatomical location on ultrasonography but scintigraphy did not identify functional tissue in one patient. In the 12 transitory CH patients, a normally shaped thyroid was detected by ultrasound in the usual location, whereas scintigraphy showed absence of functional tissue in two identical twins and scarce concentration of isotope in a third patient. CONCLUSION: Ultrasonography is an accurate method to establish the presence of dysgenesis and might be used as the first imaging tool in patients with CH, whereas scintigraphy should be used mainly to distinguish agenesis from ectopia. Further examination is required to differentiate permanent CH with a normally located and shaped gland from transitory hypothyroidism.

Doppler ultrasonography for the detection of renal artery stenosis in transplanted kidneys.

The objective of this study was to evaluate the importance of Doppler ultrasonography in diagnosing renal artery stenosis in transplanted kidneys using angiography as the accepted gold standard. Fourteen kidney graft recipients with clinical severe hypertension, impaired renal function, or both had their renal artery blood flow studied by Doppler ultrasonography before angiography. Seven patients had renal artery stenosis diagnosed by angiography. In six of them, the same diagnosis was achieved by Doppler ultrasonography, and in one patient, Doppler ultrasonography and angiography showed total occlusion of the renal artery. In six patients, both exams were normal. The only false-negative result was in an 8-year-old patient whose graft was placed in the left flank. The Doppler ultrasonography specificity was 100% and its sensitivity was 87.5%. The predictive value of a positive test was 100%; the predictive value of a negative test was 85.7%. Doppler ultrasonography of the renal artery in transplanted kidneys showed an accuracy of 92.86% in diagnosing renal artery stenosis. Because the technique is noninvasive, it should be considered as a first-line screening test.