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The widely reported association between ADHD and overweight may be attributable to genetic and environmental factors also present in unaffected family members. Therefore, the purpose of this study was to examine the association between ADHD and overweight within families. A cohort was used of families with at least one member with ADHD, recruited as part of the Dutch node of the International Multicenter ADHD Genetics (IMAGE) study, with assessments taking place between 2003 and 2006, 2009 and 2012, and 2013 and 2015. The three assessment waves yielded N = 1828 youth assessments and N = 998 parent assessments from N = 447 unique families. Overweight was defined as a body mass index (BMI) ≥ 85th percentile for youth of the same age and sex; overweight in adults as a BMI ≥ 25. Effects of age, gender, and medication use (psychostimulants, antipsychotics, and melatonin) were taken into account. Generalized estimation equations were used to correct for within-family and within-subject correlations. There was no difference in risk between ADHD-affected youth and their unaffected siblings (OR 0.92, 95% CI 0.78–1.09). However, compared to population prevalence data, all ADHD family members alike were at increased risk for being overweight: ADHD-affected youth (OR 1.33, 95% CI 1.13–1.59), unaffected siblings (OR 1.73, 95% CI 1.45–2.08), mothers (OR 1.74, 95% CI 1.40–2.17) and fathers (OR 1.78, 95% CI 1.46–2.15). Parental overweight—but not parental ADHD—was predictive of offspring overweight (mothers OR 1.40; 95% CI 1.14–1.73, fathers OR 1.83; 95% CI 1.41–2.36). Being overweight runs in ADHD families, yet is not specifically linked to ADHD within families. Shared unhealthy lifestyle factors (including nutrition, sleep, exercise, stress) as well as genetic factors shared by family members likely explain the findings. Electronic supplementary material The online version of this article (10.1007/s00787-019-01331-7) contains supplementary material, which is available to authorized users.

Objective To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD). Design Nationwide, cross-sectional study. Methods Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1 January 1995 and 1 January 2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing. Results During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25 642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53, 16 and 16%, respectively). Conclusion Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis.

Summary: Several studies indicate that low plasma levels of thyroid hormone shift the hemostatic system towards a hypocoagulable and hyperfibrinolytic state, whereas high levels of thyroid hormone lead to more coagulation and less fibrinolysis. Low levels of thyroid hormone thereby seem to lead to an increased bleeding risk, whereas high levels, by contrast, increase the risk of venous thromboembolism. Hypothyroidism leads to a higher incidence of acquired von Willebrand's syndrome and with increasing levels of free thyroxine, levels of fibrinogen, factor VIII and von Willebrand factor, amongst others, increase gradually, to the extent that they may lead to symptomatic venous thromboembolism in patients with hyperthyroidism. Here, we discuss the literature on the effect of thyroid hormone on the hemostatic system and the associated risk of bleeding and venous thromboembolism. Patients with hypothyroidism are at increased risk of developing bleeding complications, which could be relevant in patients undergoing invasive procedures. Furthermore, physicians should be aware of the possibility of hyperthyroidism as an underlying risk factor for venous thromboembolism, especially in unexplained cases. Clinical studies are needed to further investigate the significance for general practice of these findings. Besides the effects of hyperthyroidism on venous thromboembolism, its effects on embolism secondary to atrial fibrillation are described.

Human and animal studies increasingly point toward a neural pathogenesis of the metabolic syndrome, involving hypothalamic and autonomic nervous system dysfunction. We hypothesized that increased very-low-density lipoprotein-triglyceride (VLDL-TG) secretion by the liver in a rat model for dyslipidemia, that is, the obese Zucker (fa/fa) rat, is due to relative hyperactivity of sympathetic, and/or hypoactivity of parasympathetic hepatic innervation. To test the involvement of the autonomic nervous system, we surgically denervated the sympathetic or parasympathetic hepatic nerve in obese Zucker rats. Our results show that cutting the sympathetic hepatic nerve lowers VLDL-TG secretion in obese rats, finally resulting in lower plasma TG concentrations after 6 weeks. In contrast, a parasympathetic denervation results in increased plasma total cholesterol concentrations. The effect of a sympathetic or parasympathetic denervation of the liver was independent of changes in humoral factors or changes in body weight or food intake. In conclusion, a sympathetic denervation improves the lipid profile in obese Zucker rats, whereas a parasympathetic denervation increases total cholesterol levels. We believe this is a novel treatment target, which should be further investigated.

SummaryObjective Osteocalcin is a well-known marker of bone formation. Recently, mice lacking osteocalcin or its receptor were reported to be subfertile with low testosterone and high luteinizing hormone concentrations. In parallel, in humans, a loss-of-function mutation of the osteocalcin receptor was associated with hypergonadotropic hypogonadism. This suggests that osteocalcin is necessary for normal pituitary-gonadal axis function. Our objective was to determine the association between physiological variations in osteocalcin and the pituitary-gonadal axis in older men. Design and patients Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a representative sample of the older Dutch population (65–88 years). Measurements Serum levels of total (T), free (FT) and bioavailable (bioT) testosterone, luteinizing hormone (LH) and osteocalcin were determined. Data were analysed using linear regression analyses and adjusted for age, BMI, 25-hydroxyvitamin D, parathyroid hormone and vitamin K antagonist use. Results A total of 614 men participated in the study. The median age was 75·4 (69·8–81·2) years, and the median osteocalcin level was 1·8 (1·3–2·4) nmol/l. Serum osteocalcin was inversely associated with FT (adjusted B = −0·22 ± 0·09 ng/dl, P = 0·012) and bioT (adjusted B = −0·26 ± 0·08 nmol/l, P

Item does not contain fulltext We studied 261 ADHD probands and 354 of their siblings to assess quantitative trait loci associated with autism spectrum disorder symptoms (as measured by the Children's Social Behavior Questionnaire (CSBQ)) using a genome-wide linkage approach, followed by locus-wide association analysis. A genome-wide significant locus for the CSBQ subscale addressing social interaction was found on chromosome 7q11, with suggestive signals supporting this locus on three other CSBQ subscales. We identified two other suggestive loci for the CSBQ total scale and individual subscales on chromosomes 4q35 and 7p12. Fine-mapping the significantly linked locus resulted in interesting candidate genes, although their association was not significant after permutation testing.

Objective Bariatric surgery has rapid metabolic effects on glucose metabolism before the occurrence of clinically significant weight loss. This suggests an acute effect of the surgery itself, e.g., resulting from bypassing the nutrient flow from the proximal gastrointestinal tract. Rapid effects of Roux-en-Y gastric bypass surgery (RYGB) on glucose metabolism were defined. Design and Methods Glucose metabolism and total triglyceride hydrolysis in the basal state and during a hyperinsulinemic euglycemic clamp using stable isotopes 2 weeks were studied before and after RYGB. Results Eighteen pre-menopausal women scheduled for RYGB were included. 2 weeks after RYGB median weight loss was 7.8 kg. Basal insulin and glucose levels decreased after surgery. Endogenous glucose production (EGP) was lower after surgery. In addition, insulin levels were lower during the clamp after surgery, suggesting enhanced clearance. Hepatic and peripheral insulin sensitivity did not change. Free fatty acid (FFA) levels increased after surgery both in the basal state and during the first step of the clamp. Total triglyceride hydrolysis did not change in the basal state and tended to be higher during hyperinsulinemia. Conclusions Within 2 weeks, RYGB reduces basal EGP as well as insulin and glucose levels without an acute beneficial effect on hepatic or peripheral insulin sensitivity. The latter may be explained by higher rates of lipolysis and exposure to FFA induced by the hypocaloric state.

SummaryObjective Male patients with the X-linked IGSF1 deficiency syndrome are characterized by central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency and occasionally transient partial growth hormone deficiency. Thyroid hormone plays a vital role in brain development and functioning, and while most patients receive adequate replacement therapy starting shortly after birth, it is unknown whether this syndrome is accompanied by long-term impaired cognitive functioning. We therefore assessed cognitive functioning in male patients with IGSF1 deficiency. Methods Fifteen adult male patients with IGSF1 deficiency participated in neuropsychological assessment of executive functioning and memory, and completed validated questionnaires on health-related quality of life (HRQoL), mood and fatigue. Results were compared to data from previous studies by our department: 54 healthy controls (76 for the attention task) for the test battery and 191 healthy controls for the questionnaires. Results All patients had central hypothyroidism, and twelve were treated with levothyroxine. Patients performed worse than controls in tasks that required attentional control (Trail Making Test, Letter-Digit Substitution Test, and Sustained Attention to Response Task) (all P < 0·001). Memory was unaffected. In addition, patients reported more mental fatigue and reduction of activity (Multidimensional Fatigue Inventory) (both P < 0·01), while HRQoL and mood reports were not different from controls. Age at the start of replacement therapy and current thyroxine levels were not related to outcome. Conclusions Adult male patients with IGSF1 deficiency exhibit mild deficits in attentional control on formal testing. This finding was not related to the age at start of replacement therapy, or current levothyroxine treatment.

Many children with attention deficit/hyperactivity disorder (ADHD) show symptoms of Autism Spectrum Disorders (ASD), especially problems in reciprocal social interaction (Nijmeijer et al., 2008b). Studies in community twin samples ADHD and ASD have shown that a substantial part of genetic influences are shared between ADHD and ASD (Reiersen, Constantino, Grimmer, Martin, & Todd, 2008; Ronald, Simonoff, Kuntsi, Asherson, & Plomin, 2008); our own study confirmed the familiality of ASD symptoms in children with ADHD and their siblings (Nijmeijer et al., 2008a). Moreover, genetic linkage studies have indentified overlapping sets of suggestive disease loci for ADHD and ASD, (e.g., Faraone et al., 2005; Waldman & Gizer, 2006; Yang & Gill, 2007). Addressing ASD symptoms in children with ADHD may be particularly useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD. That is, non-replicated findings may be due to the heterogeneity of ADHD, which may partly stem from presence or absence of ASD symptoms (Mulligan et al., 2009; Nijmeijer et al., 2008). The serotonin transporter gene (SLC6A4/SERT/5-HTT) and catechol O-methyltransferase (COMT) are interesting candidate genes for the study of ASD symptoms in children with ADHD, as both have been implicated not only in ADHD (e.g., Gizer, Ficks, & Waldman, 2009), but also in autism (e.g., Huang & Santangelo, 2008; James et al., 2006). SLC6A4 contains a 44 bp deletion/insertion functional polymorphism in the promoter region, called 5-HTTLPR. In a recent meta-analysis for 5-HTTLPR in ADHD, a significant association was found between the long (L) allele and ADHD (Gizer et al., 2009). On the other hand, a slight majority of studies has indicated the short (S) allele as the ASD risk allele (for reviews see Devlin et al., 2005; Huang & Santangelo, 2008). Animal studies have shown that serotonin is important in the regulation of attention and response control (Gainetdinov et al., 1999; Wistanley et al., 2005). Deficiencies herein are reported for both ADHD and ASD (e.g. Geurts et al., 2004; Happe et al., 2006). Involvement of serotonin in ASD is further supported by its role in early neurodevelopment (Whitaker-Azmitia, 2001), by findings of elevated platelet serotonin levels (Anderson et al., 2002; Mulder et al., 2004), the effectiveness of selective serotonin reuptake inhibitors in the treatment of ASD symptoms (Kolevzon, Mathewson, & Hollander, 2006), and the association between 5-HTTLPR and cortical gray matter volumes (Wassink et al., 2007). COMT contains a single nucleotide polymorphism (SNP) resulting in either valine or methionine encoding alleles (Val158Met). A decreased COMT activity is associated with the Met-allele. In the prefrontal cortex (PFC), this reduced enzyme activity is thought to increase dopamine levels. Research in ADHD patients suggests that the PFC functions inefficiently in the presence of the Val allele (high activity COMT; Blasi et al., 2005; Boonstra et al., 2008), and some studies found that the Val158Met polymorphism was associated with stimulant response in children with ADHD (e.g., Kereszturi et al., 2008). Despite the potential relevance of this polymorphism to the etiology of ADHD, two meta-analyses found no association between ADHD and the Val158Met SNP (Cheuk & Wong, 2006; Gizer et al., 2009). In a recent study, Caspi et al. (2008) concluded that the association may apply only to those children with ADHD who show comorbid antisocial behavior. Palmason et al. (2010) could not confirm this association, although they did find an association between the COMT Val158Met SNP and ADHD. COMT may be an interesting candidate gene for ASD, as inefficient PFC functioning is also implicated in ASD (e.g. Geurts et al., 2004), and dopamine antagonists, such as risperidone, improve some aspects of autism, such as irritability (e.g., McCracken et al., 2002) and executive functioning (Troost et al., 2006). Only two studies to date have addressed the association between COMT and ASD (James et al., 2006; Yirmiya et al., 2001). Yirmiya et al. found no association, whereas James et al. reported the overrepresentation of the COMT Val-allele in children with autism as compared to normal control children. Apart from genetic influences, a range of environmental factors are important in the etiology of ADHD, of which maternal smoking during pregnancy and low birth weight have been the most consistently replicated (Bhutta, Cleves, Casey, Cradock, & Anand, 2002; Langley, Rice, van den Bree, & Thapar, 2005; Linnet et al., 2003). Both are also found to be autism risk factors (Hultman, Sparen, & Cnattingius, 2002; Kolevzon, Gross, and Reichenberg, 2007). Not taking different levels of exposure to these risk factors into account may, in addition to clinical heterogeneity, explain inconsistent association study results for SLC6A4 and COMT in ADHD. This follows from the notion of gene environment (GxE) interactions, i.e., only in the presence of a certain environmental risk factor may a genotype contribute to an increased risk for a disorder. One previous study has reported significant interaction between COMT and birth weight, i.e., for antisocial behaviour in children with ADHD (Thapar et al., 2005). Sengupta et al. (2006), though, could not replicate this finding. The interaction of low birth weight and maternal smoking during pregnancy with SLC6A4 was investigated by Langley et al. (2008), who did not find significant effects on a diagnosis of ADHD, nor on associated antisocial behavior. Clearly, addressing GxE interactions in ADHD and ASD has only recently been started and requires much more study. In the current study, we investigated main and interaction effects of COMT, SLC6A4, maternal smoking during pregnancy, and low birth weight on ASD symptoms in children with ADHD in the Dutch subsample of the International Multicenter ADHD Genetics (IMAGE) study. We continued previous work on SLC6A4 and COMT in the IMAGE sample, in which no association between 5-HTTLPR and ADHD (Xu et al., 2008), and between COMT Val158Met and ADHD (Brookes et al., 2006) was found. ASD symptoms were measured with the Children's Social Behavior Questionnaire (CSBQ; Hartman, Luteijn, Serra, & Minderaa, 2006), that was only available for the Dutch subsample of IMAGE. The CSBQ is an instrument particularly suited to measure the continuous distribution of ASD traits in the population as well as in clinical groups other than ASD (Hartman et al., 2006; Luteijn et al., 2000). All analyses were repeated in an independent Dutch ADHD sample for replication, consisting of children who participated in the TRacking Adolescents' Individual Lives Survey (TRAILS; Huisman et al., 2008).

Contains fulltext : 87878.pdf (Publisher’s version ) (Closed access) OBJECTIVE: : Children with attention-deficit hyperactivity disorder (ADHD) frequently experience comorbid motor problems, developmental coordination disorder. Also, children with ADHD are said to overestimate their abilities in the cognitive and social domain, the so-called "Positive Illusory Bias." In this cross-sectional study, the relationship between actual motor performance and perceived motor competence was examined. METHOD: Motor performance was assessed using the Movement Assessment Battery for Children in 100 children and adolescents (age 6-17 years), including 32 children with ADHD combined type, 18 unaffected siblings, and 50 healthy control children. ADHD was diagnosed using Parent and Teacher questionnaires and a clinical interview. Perceived motor competence and interest in the motor domain were rated with the Dutch supplement scale to Harters' Self-Perception Profile for Children, especially focusing on the motor domain (m-CBSK). RESULTS: Children with ADHD had poorer motor performance than unaffected siblings and control children, especially in the field of manual dexterity. However, no relationship was found between motor performance and perceived motor competence. Only children with the very lowest motor performance had a significantly lowered perception of their motor competence. Interest in the motor domain and motor self-perception was positively correlated. CONCLUSION: Children with ADHD performed poorer on the Movement Assessment Battery for Children, but generally overestimated their own motor competence. 01 januari 2010

Contains fulltext : 79647.pdf (Publisher’s version ) (Closed access) BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is frequently accompanied by motor problems (MPs). We investigated a possible shared etiology between the two traits in the Dutch sample of the International Multicenter ADHD Genetics study comprising 275 children with ADHD and their affected or unaffected sibling and 146 unrelated control children. METHOD: Exploratory data analysis and bivariate structural equation modeling were used to estimate the familiality of MP rated by parents (Developmental Coordination Disorder Questionnaire [DCD-Q]) or teachers (Groningen Motor Observation Scale [GMO]) and to determine the familial and environmental correlation between MP and ADHD. Furthermore, the nature of the familiality was explored by studying the siblings of ADHD-affected children. RESULTS: The ADHD-affected children had significantly more MP than their unaffected siblings, who in turn had significantly more MP than the control subjects. The familial component of MP measured by DCD-Q and GMO was 47% and 22%, respectively. The familial correlation between motor performance measures and ADHD was -0.38 for DCD-Q and -0.40 for GMO. Our data suggested that co-occurrence of ADHD and MP possibly marks a distinct subtype of ADHD, rather than signaling increased severity of disease. CONCLUSIONS: Attention-deficit/hyperactivity disorder and MP have a common basis that may be due to genetic factors and/or shared environmental factors. Attention-deficit/hyperactivity disorder accompanied by MP may behave like a distinct subtype of ADHD, but more research will be needed to support that hypothesis.

Contains fulltext : 71316.pdf (Publisher’s version ) (Closed access) Fecal incontinence is a common disorder in children. Many children with fecal incontinence have psychosocial co-morbidity. In this study, the effect of psychosocial co-morbidity on the treatment outcome of children with fecal incontinence was evaluated. One hundred and fifty children with fecal incontinence were treated in a multidisciplinary program. All children had been treated unsuccessfully for at least one year before entering the program. The treatment consisted of laxative treatment, psychosocial interventions, and biofeedback training. Psychosocial co-morbidity was classified according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). One hundred and forty-one children were completely analyzed (102 boys, mean age 9.6 (range 6.5-16.5) years). Of these, 31 (22%) children had fecal incontinence without constipation and 110 (78%) children had fecal incontinence associated with constipation. In 95% of children, at least one psychosocial co-morbidity was present. Treatment was successful at 12 months in 69% of patients. Treatment was less successful in children with attention deficit hyperactivity disorder (ADHD), in children with parent-child relational problems, and in mentally retarded children. The results indicate that the early assessment and treatment of psychosocial co-morbidity might improve treatment response in children with fecal incontinence. Children with fecal incontinence are treated less successfully in the first year if they have ADHD, parent-child relational problems, or mental retardation. Psychosocial evaluation and the early assessment and treatment of psychosocial co-morbidity is indicated in order to improve response rate. Family counseling--aimed at improving parent-child relations--should be an integral part of a multidisciplinary treatment program for fecal incontinence.

Defective control of endogenous glucose production is an important factor responsible for hyperglycaemia in the diabetic individual. During the past decade, progressively more evidence has appeared indicating a strong and potentially causal relationship between disturbances of the circadian system and defects of metabolic regulation, including glucose metabolism. The detrimental effects of disturbed circadian rhythms may have their origin in disturbances of the molecular clock mechanisms in peripheral organs, such as the pancreas and liver, or in the central brain clock in the hypothalamic suprachiasmatic nuclei (SCN). To assess the role of SCN output per se on glucose metabolism, we investigated (i) the effect of several SCN neurotransmitters on endogenous glucose production and (ii) the effect of SCN neuronal activity on hepatic and systemic insulin sensitivity. We show that silencing of SCN neuronal activity results in decreased hepatic insulin sensitivity and increased peripheral insulin sensitivity. Furthermore, both oxytocin neurones in the paraventricular nucleus of the hypothalamus (PVN) and orexin neurones in the lateral hypothalamus may be important targets for the SCN control of glucose metabolism. These data further highlight the role of the central clock in the pathophysiology of insulin resistance.

The water deprivation test is the gold standard test to differentiate central or nephrogenic diabetes insipidus (DI) from primary polydipsia (PP) in patients with polyuria and polydipsia. Few studies have addressed the diagnostic performance of this test. The aim of this retrospective cohort study was to evaluate the diagnostic performance of the standard water deprivation test, including plasma arginine vasopressin (AVP) measurements, in 40 consecutive patients with polyuria. We compared initial test results with the final clinical diagnosis, i.e., no DI, central DI, or nephrogenic DI. The median length of follow-up was 8 years. In a subset of ten patients, the novel marker copeptin (CP) was measured in plasma. Using the final diagnosis as a gold standard, a threshold for urine osmolality of >800 mOsmol/kg after water deprivation yielded a sensitivity and specificity of 96 and 100%, respectively, for diagnosing PP. Sensitivity increased to 100% if the cut-off value for urine osmolality was set at 680 mOsmol/kg. Plasma AVP levels did not differ between patient groups and did not differentiate among central DI, nephrogenic DI, or PP. In all three patients with central DI, plasma CP was 290 mOsmol/kg, and >2.5 pmol/l in patients without DI. The optimal cut-off value for differentiating PP from DI during a water deprivation test was urine osmolality >680 mOsmol/kg. Differentiating between central and nephrogenic DI should be based on clinical judgment as AVP levels did not discriminate.

BACKGROUND: Cranial radiation therapy (CRT) is required for successful treatment of a variety of brain tumours in childhood. OBJECTIVE: To investigate whether childhood CRT leads to altered sleep-wakefulness organization in adulthood, and to identify the determinants of such alterations. SUBJECTS AND METHODS: Subjective (questionnaires) and objective (actigraphy) measures of circadian rhythmicity and sleep were assessed in 25 individuals, 8-29 years after CRT for medulloblastoma (n=17) or other intracranial tumours (n=8), and in a group of 34 age-matched healthy individuals. Serum GH peak during insulin-induced hypoglycaemia and serum concentrations of prolactin and leptin (expressed per fat mass) were determined in the CRT group. RESULTS: The CRT group showed a markedly increased sleep duration (8.66 h, compared with 7.66 h in controls). In addition, the sleep-wake rhythm showed greater amplitude and less fragmentation, and less tolerance for alterations in the timing of sleep. Regression analysis showed both radiation dosage and neuroendocrine status to be determinants of sleep changes, suggesting that some of the alterations may be normalized with hormone supplementation. CONCLUSION: The present study shows that high-dose cranial radiation therapy in childhood is associated with objective and subjective changes in the sleep-wake rhythm in adulthood.

Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.

Rats on different free-choice (fc) diets for 1 week of either chow, saturated fat and liquid sugar (fcHFHS), chow and saturated fat (fcHF), or chow and liquid sugar (fcHS) have differential levels of neuropeptide Y (NPY) mRNA in the arcuate nucleus. Because these differences were not explained by plasma leptin levels but did predict subsequent feeding behaviour, in the present study, we first examined whether leptin sensitivity could explain these differences. Second, we focused on the role of NPY on feeding behaviour, and measured NPY mRNA levels and sensitivity to NPY after 4 weeks on the different choice diets. To determine leptin sensitivity, we measured food intake after i.p. leptin or vehicle injections in male Wistar rats subjected to the fcHFHS, fcHS, fcHF or Chow diets for 7 days. Next, we measured levels of arcuate nucleus NPY mRNA with in situ hybridisation in rats subjected to the choice diets for 4 weeks. Finally, we studied NPY sensitivity in rats subjected to the fcHFHS, fcHS, fcHF or Chow diet for 4 weeks by measuring food intake after administration of NPY or vehicle in the lateral ventricle. Leptin decreased caloric intake in rats on Chow, fcHS and fcHF but not in rats on the fcHFHS diet. After 4 weeks, rats on the fcHFHS diet remained hyperphagic, whereas fcHS and fcHF rats decreased caloric intake to levels similar to rats on Chow. By contrast to 1 week, after 4 weeks, levels of NPY mRNA were not different between the diet groups. Lateral ventricle administration of NPY resulted in higher caloric intake in fcHFHS rats compared to rats on the other choice diets or rats on Chow. Our data show that consuming a combination of saturated fat and liquid sugar results in leptin resistance and increased NPY sensitivity that is associated with persistent hyperphagia.

In patients with hyperprolactinemia, the thyrotropin-releasing hormone (TRH) stimulation test is widely applied to distinguish prolactinoma from other causes of hyperprolactinemia. In the present study, we established reference values for the plasma concentration of prolactin (PRL) and its response to TRH. Basal PRL and the PRL response to 400 micrograms TRH i.v. was determined in 50 subjects recruited from the general population, equally distributed according to sex and age between 20 and 69 years. PRL was determined by a fluoroimmunometric assay. Reference values are given as the observed range. Plasma concentrations of PRL were 4.0-25 micrograms/l (median: 10.0 micrograms/l) in women and 0.5-19.0 micrograms/l (median: 8.5 micrograms/l) in men (p = 0.11). The peak PRL concentration after stimulation with TRH was slightly higher in women (median: 51 micrograms/l) than in men (median: 41 micrograms/l; p = 0.04) and was reached at t = 20 min in all subjects. The relative increase in plasma PRL (median: 440%) did not show a statistically significant effect of age or sex. In 12 subjects (24%), the relative increase in plasma PRL was lower than 250%, which has traditionally been considered the minimum cutoff for a normal response. There were no effects of smoking and alcohol, but regular ingestion of liquorice was associated with lower basal (p = 0.03) and lower stimulated (p = 0.05) plasma concentrations of PRL. The present study provides reference values for basal and TRH-stimulated plasma concentrations of PRL

Background: For diagnostic tests used in the evaluation of patients with Cushing's syndrome, well defined reference values were lacking in our laboratory. In the present study, we established reference values based upon test results of 50 subjects recruited from the general population. Methods: We studied 50 subjects not suspected of having Cushing's syndrome, equally distributed according to sex and age between 20 and 69 years. In addition to 24 h urinary excretion of free cortisol for two days, a low-dose (1 mg) overnight dexamethasone suppression test, a corticotropin releasing hormone stimulation test (CRH test) and a high-dose (7 mg) intravenous dexamethasone suppression test were performed. Reference values are given as the observed range. Results: There was considerable intra-subject variation in 24 h urinary cortisol excretion which could not be merely attributed to incompleteness of the urine collection. The following reference values were established: 24 h urinary free cortisol excretion: 15–145 nmol/24 h; overnight dexamethasone suppression test: cortisol on day 2

Item does not contain fulltext OBJECTIVE: Although hyperactivity would seem to increase energy expenditure, attention-deficit hyperactivity disorder (ADHD) appears to increase the risk for being overweight. This study examined the body mass index (BMI) in children with ADHD and its relationship with age, gender, ADHD and comorbid symptom severity, inhibitory control, developmental coordination disorder, sleep duration, and methylphenidate use. METHOD: Participants were 372 Dutch children with ADHD combined type aged 5 to 17 years participating in the International Multicenter ADHD Genetics (IMAGE) study. We categorized BMI according to international age- and gender-specific reference values and calculated BMI-standard deviation scores (BMI-SDS). The control population was matched for age, gender, and ethnicity and originated from the same birth cohort as the ADHD group. Inhibitory control was measured by the computerized Stop-signal task. Prevalence differences of underweight, overweight, and obesity between groups were expressed in odds ratios. We used linear regression analyses with gender, age, parent- and teacher-rated ADHD and comorbid scores, inhibitory control, sleep duration, motor coordination, and methylphenidate use to predict BMI-SDS. RESULTS: Boys with ADHD aged 10 to 17 years and girls aged 10 to 12 years were more likely to be overweight than children in the general Dutch population. Younger girls and female teenagers, however, seemed to be at lower risk for being overweight. Higher oppositional behavior and social communication problems related to higher BMI-SDS scores, whereas more stereotyped behaviors related to lower BMI-SDS scores. We found no effects of the other examined associated risk factors on BMI-SDS. CONCLUSIONS: Attention-deficit hyperactivity disorder in boys is a risk factor for overweight. In girls with ADHD, the prevalence of overweight is age dependent and most pronounced in girls aged 10 to 12 years. They have a 4-fold risk of being obese. Higher oppositional and social communication problems pose an increased risk for overweight, whereas sleep duration, motor coordination problems, and methylphenidate use do not.

Item does not contain fulltext OBJECTIVES: Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD may identify a sample of reduced genetic heterogeneity. METHODS: Children with ADHD from the International Multicentre ADHD Genetic (IMAGE) study were evaluated with the Parental Account of Children's Symptoms. Genetic association testing was performed in PLINK on 890 probands with genome-wide genotyping data. Bioinformatics enrichment-analysis was performed on highly ranked findings. Further characterization of the findings was conducted in 313 Dutch IMAGE children using the Developmental Coordination Disorder Questionnaire (DCD-Q). RESULTS: Although none of the findings reached genome-wide significance, bioinformatics analysis of the top-ranked findings revealed enrichment of genes for motor neuropathy and amyotrophic lateral sclerosis. Genes involved in neurite outgrowth and muscle function were also enriched. Among the highest ranked genes were MAP2K5, involved in restless legs syndrome, and CHD6, causing motor coordination problems in mice. Further characterization of these findings using DCD-Q subscales found nominal association for 15 SNPs. CONCLUSIONS: Our findings provide clues about the aetiology of motor coordination problems, but replication studies in independent samples are necessary. 01 maart 2012

Context: The sympathetic nervous system (SNS) controls bone turnover in rodents, but it is uncertain whether a similar role for the SNS exists in humans. Pheochromocytomas are catecholamine-producing neuroendocrine tumors. Because catecholamines are the neurotransmitters of the SNS, we hypothesized that pheochromocytoma patients have increased bone turnover. Objective: Our objective was to compare bone turnover in pheochromocytoma patients and controls. Design and Setting: This retrospective case-control study was performed at the Endocrine Department of the Academic Medical Center of the University of Amsterdam in The Netherlands from 2007 until 2011. Patients: All patients were screened for pheochromocytoma. Cases (n = 21) were identified by 24-h urinary excretion of fractionated metanephrines above the institutional reference value and confirmed by histology after adrenalectomy. All patients screened and diagnosed as not having pheochromocytoma served as controls (n = 126). Main Outcome Measure: The difference in bone turnover markers C-terminal cross-linking telopeptides of collagen type I (CTx) and procollagen type 1 N propeptide (P1NP) between cases and controls was the main outcome measure. Results: CTx concentrations were higher in cases [343 ng/liter; interquartile range (IQR), 295 ng/liter] than in controls (232 ng/liter; IQR, 168 ng/liter; P

Contains fulltext : 97999.pdf (Publisher’s version ) (Closed access) Context: Venous thrombosis has frequently been reported in patients with endogenous Cushing's syndrome (CS). Objective: The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. Design and Setting: We conducted a multicenter cohort study at all university medical centers in The Netherlands. Patients: Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. Main Outcome Measures: We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. Results: A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). Conclusions: Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

BackgroundFamilial neurohypophyseal (central) diabetes insipidus (DI) is caused by mutations in the arginine vasopressin–neurophysin II (AVP–NPII) gene. The majority of cases is inherited in an autosomal dominant way. In this study, we present the clinical features of a mother and her son with autosomal dominant neurohypophyseal DI caused by a novel mutation.CaseA thirty-four-year-old woman and her three-year-old son were evaluated because of polyuria and polydipsia since the age of 1.5 years onwards. Both patients were subjected to a water deprivation test confirming the diagnosis of central DI. Magnetic resonance imaging of the brain of the mother showed a hypothalamus without apparent abnormalities and a relatively small neurohypophysis without a hyperintense signal. Mutation analysis showed a c.322G>T (p.?/p.Glu108X) in Exon 2 of the AVP–NPII gene in both mother and son.DiscussionThis study reports neurohypophyseal DI in a mother and her son due to a novel mutation in Exon 2 of the AVP–NPII gene. Clinical and pathophysiological aspects of this disease are shortly reviewed and discussed.

Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E-03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Contains fulltext : 88211.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. METHOD: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD and 1,453 siblings were analyzed. The total and subscale scores of the Social Communication Questionnaire (SCQ) were used as quantitative traits for multipoint regression-based linkage analyses on 5,407 autosomal single-nucleotide polymorphisms applying MERLIN-regress software, both without and with inclusion of ADHD symptom scores as covariates. RESULTS: The analyses without ADHD symptom scores as covariates resulted in three suggestive linkage signals, i.e., on chromosomes 15q24, 16p13, and 18p11. Inclusion of ADHD symptom scores as covariates resulted in additional suggestive loci on chromosomes 7q36 and 12q24, whereas the LOD score of the locus on chromosome 15q decreased below the threshold for suggestive linkage. The loci on 7q, 16p, and 18p were found for the SCQ restricted and repetitive subscale, that on 15q was found for the SCQ communication subscale, and that on 12q for the SCQ total score. CONCLUSIONS: Our findings suggest that QTLs identified in this study are ASD specific, although the 15q QTL potentially has pleiotropic effects for ADHD and ASD. This study confirms that genetic factors influence ASD traits along a continuum of severity, as loci potentially underlying ASD symptoms in children with ADHD were identified even though subjects with autism had been excluded from the IMAGE sample, and supports the hypothesis that differential genetic factors underlie the three ASD dimensions. 01 juli 2010

Contains fulltext : 80806.pdf (Publisher’s version ) (Closed access) Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3' untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains.

BACKGROUND: Motor problems occur in 30% to 50% of children with ADHD, and have a severe impact on daily life. In clinical practice there seems to be little attention for this comorbidity with the possible consequence that these motor problems go undertreated. METHOD: Clinical interview and questionnaire survey of treatment by physiotherapy and factors predicting treatment of motor problems in 235 children with ADHD and 108 controls. RESULTS: Half of motor-affected children had received physiotherapy. Treated children had more severe motor problems, and less frequently presented with comorbid anxiety and conduct disorder. Treated and untreated children were similar in age, and rated similarly on ADHD inattentive and hyperactive-impulsive scales and parental socio-economic status. CONCLUSION: Currently, undertreatment of motor problems in ADHD occurs. Behavioural factors play a role in referral and intervention.

SUMMARY Objective: The type 2 deiodinase (D2)-Thr92Ala polymorphism has been associated with decreased D2 activity in some in vitro experiments but not in others. So far no association between the D2-Thr92Ala polymorphism and serum thyroid hormone levels has been observed in humans, but in a recent study in athyroid patients, it was suggested that patients homozygous for the Ala(92) allele needed higher thyroxine doses to achieve TSH suppression. We studied the association between the D2-Thr92Ala polymorphism with thyroid hormone levels and thyroxine dosage, in patients treated for differentiated thyroid carcinoma (DTC) and in a group of patients treated for Hashimoto thyroiditis. Design: Cross sectional study Patients: We studied 156 patients with DTC treated with TSH suppressive thyroid hormone replacement therapy for longer than 3 years and 141 patients with Hashimoto thyroiditis treated for at least 6 months with thyroxine. Measurements: In all patients, serum levels of TSH, free thyroxine, triiodothyronine and reverse T3 were measured and genotypes of the D2-Thr92Ala polymorphism were determined by Taqman assay. Univariate regression analysis was performed to determine the relation between thyroxine dosages and the D2-Thr92Ala polymorphism corrected for age, gender, BMI and serum TSH levels. Results: Both in DTC patients and Hashimoto patients, no association was observed between serum thyroid hormone levels or thyroxine dosages in presence of the D2-Thr92Ala polymorphism. Categorization of DTC patients according to degree of TSH suppression did not change these results. Conclusion: The D2-Thr92Ala polymorphism is not associated with thyroid hormone levels or thyroxine dose in patients treated for DTC or Hashimoto thyroiditis

We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)—and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively different phenotype than ADHD without comorbid problems. An EF—and a motor-endophenotype were formed based on nine neuropsychological tasks administered to 816 children from ADHD—and control-families. Additional data on comorbid problems were gathered using questionnaires. Results indicated that oppositional defiant behaviors appeared the most important comorbid problems of ADHD, followed by autistic traits, and than followed by motor coordination problems, anxiety, and reading problems. Both the EF—and motor-endophenotype were correlated and cross-correlated in siblings to autistic traits, motor coordination problems and reading problems, suggesting ADHD and these comorbid problems may possibly share familial/genetic EF and motor deficits. No such results were found for oppositional defiant behaviors and anxiety. ADHD in co-occurrence with comorbid problems may not be best seen as a distinct subtype of ADHD, but further research is warranted. Electronic supplementary material The online version of this article (doi:10.1007/s10802-009-9312-6) contains supplementary material, which is available to authorized users.

Contains fulltext : 81682.pdf (Publisher’s version ) (Closed access) The aims of this study were to investigate whether subtle PDD symptoms in the context of ADHD are transmitted in families independent of ADHD, and whether PDD symptom familiality is influenced by gender and age. The sample consisted of 256 sibling pairs with at least one child with ADHD and 147 healthy controls, aged 5-19 years. Children who fulfilled criteria for autistic disorder were excluded. The Children's Social Behavior Questionnaire (CSBQ) was used to assess PDD symptoms. Probands, siblings, and controls were compared using analyses of variance. Sibling correlations were calculated for CSBQ scores after controlling for IQ, ADHD, and comorbid anxiety. In addition, we calculated cross-sibling cross-trait correlations. Both children with ADHD and their siblings had higher PDD levels than healthy controls. The sibling correlation was 0.28 for the CSBQ total scale, with the CSBQ stereotyped behavior subscale showing the strongest sibling correlation (r = 0.35). Sibling correlations remained similar in strength after controlling for IQ and ADHD, and were not confounded by comorbid anxiety. Sibling correlations were higher in female than in male probands. The social subscale showed stronger sibling correlations in elder than in younger sibling pairs. Cross-sibling cross-trait correlations for PDD and ADHD were weak and not-significant. The results confirm that children with ADHD have high levels of PDD symptoms, and further suggest that the familiality of subtle PDD symptoms in the context of ADHD is largely independent from ADHD familiality.

Background: The dopamine receptor D4 (DRD4) 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by environment (G·E) interaction of the DRD4 7-repeat allele and smoking during pregnancy on ADHD and oppositional behavior in families from the International Multicenter ADHD Genetics project; and further, to test the hypothesis that the direction of effect of the DRD4 7-repeat allele differs between ADHD affected and unaffected children. Methods: Linear mixed models were used to assess main and interactive effects of the DRD4 7-repeat allele and smoking during pregnancy in 539 ADHD-affected children and their 407 unaffected siblings, aged 6–17 years. Results: There was some evidence pointing to differential effects of the DRD4 7-repeat allele on ADHD and oppositional symptoms in the affected (fewer symptoms) and unaffected children (increasing ADHD symptoms of teacher ratings). Affected children were more often exposed to prenatal smoking than unaffected children. There were limited main effects of prenatal smoking on severity of symptoms. Given the number of tests performed, no indication was found for G·E interactions. Conclusion: Despite the large sample size, no G·E interactions were found. The impact of the DRD4 7-repeat allele might differ, depending on affected status and rater. This finding is discussed in terms of differences in the activity of the dopaminergic system and of different genes involved in raterspecific behaviors. Keywords: Dopamine receptor D4 gene, attention deficit hyperactivity disorder (ADHD), maternal smoking during pregnancy, gene by environment interaction.

As part of the International Multi-centre ADHD Gene (IMAGE) project we have completed an affected sibling pair study of 142 narrowly defined DSM-IV combined type ADHD proband-sibling pairs. We found suggestive linkage on chromosomes 9 and 16 with non-parametric multipoint peak LOD scores of 2.13 and 3.1 respectively. There have been several previous ADHD linkage scans. The UCLA study (Fisher et al. 2002; Ogdie et al. 2004; Ogdie et al. 2003), the Dutch study (Bakker et al. 2003), the German study (Hebebrand et al. 2006) and the MGH Study (Faraone et al., submitted) applied the affected sib pair (ASP) strategy; the Columbian study used extended pedigrees ascertained from a population isolate (Arcos-Burgos et al. 2004). No linkage was observed on the most established ADHD linked genomic regions from these studies on 5p and 17p. The highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (LOD=3.1) overlapped with data published from UCLA (LOD>1, ~95cM) and Holland (LOD>1, ~100cM). The second highest peak in this study was on chromosome 9q22 at 90cM (LOD=2.13). Both the UCLA study and the German study also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93cM; German LOD=0.68 at 100cM). The overlap of the two main peaks from this study with those from previous studies suggests that true loci linked to ADHD may lie within these regions

Contains fulltext : 70260.pdf (Publisher’s version ) (Closed access) Behavioral genetic studies imply that salient environmental influences operate within families, making siblings in a family different rather than similar. This study is the first one to examine differential sibling experiences (as measured with the Sibling Inventory of Differential Experience) and its effect on behavioral outcomes within ADHD families. Subjects were 45 Dutch ADHD probands and their unaffected siblings (n = 45) aged 10-18 years. ADHD probands and their unaffected siblings reported differences in sibling interaction, parental treatment, and peer characteristics. These nonshared environmental influences were related to both the severity of ADHD symptoms as well as to comorbid problem behaviors. These findings suggest that environmental influences that operate within ADHD families appear relevant to the severity of problem behaviors of ADHD children and their siblings.

Contains fulltext : 70148.pdf (Publisher’s version ) (Closed access) Attention-deficit/hyperactivity disorder (ADHD) is more common in boys than in girls. It has been hypothesized that this sex difference might be related to genes on the X-chromosome, like Monoamine Oxidase A (MAOA). Almost all studies on the role of MAOA in ADHD have focused predominantly on boys, making it unknown whether MAOA also has an effect on ADHD in girls, and few studies have investigated the relationship between MAOA and neuropsychological functioning, yet this may provide insight into the pathways leading from genotype to phenotype. The current study set out to examine the relationship between MAOA, ADHD, and neuropsychological functioning in both boys (265 boys with ADHD and 89 male non-affected siblings) and girls (85 girls with ADHD and 106 female non-affected siblings). A haplotype was used based on three single nucleotide polymorphisms (SNPs) (rs12843268, rs3027400, and rs1137070). Two haplotypes (GGC and ATT) captured 97% of the genetic variance in the investigated MAOA SNPs. The ATT haplotype was more common in non-affected siblings (P = 0.025), conferring a protective effect for ADHD in both boys and girls. The target and direction of the MAOA effect on neuropsychological functioning was different in boys and girls: The ATT haplotype was associated with poorer motor control in boys (P = 0.002), but with better visuo-spatial working memory in girls (P = 0.01). These findings suggest that the genetic and neuropsychological mechanisms underlying ADHD may be different in boys and girls and underline the importance of taking into account sex effects when studying ADHD.

Contains fulltext : 69485.pdf (Publisher’s version ) (Closed access) BACKGROUND: Limited success has been achieved through previous attention-deficit/hyperactivity disorder (ADHD) linkage scans, which were all designed to map genes underlying the dichotomous phenotype. The International Multi-centre ADHD Genetics (IMAGE) project performed a whole genome linkage scan specifically designed to map ADHD quantitative trait loci (QTL). METHODS: A set of 1094 single selected Caucasian ADHD nuclear families was genotyped on a highly accurate and informative single nucleotide polymorphism (SNP) panel. Two quantitative traits measuring the children's symptoms in home and school settings were collected and standardized according to a population sample of 8000 children to reflect the developmental nature and gender prevalence difference of ADHD. Univariate linkage test was performed on both traits and their mean score. RESULTS: A significant common linkage locus was found at chromosome 1p36 with a locus-specific heritability of 5.1% and a genomewide empirical p < .04. Setting-specific suggestive linkage signals were also found: logarithm of odds (LOD) = 2.2 at 9p23 for home trait and LOD = 2.6 at 11q21 for school trait. CONCLUSIONS: These results indicate that given large samples with proper phenotypic measures, searching for ADHD genes with a QTL strategy is an important alternative to using the clinical diagnosis. The fact that our linkage region 1p36 overlaps with the dyslexia QTL DYX8 further suggests it is potentially a pleiotropic locus for ADHD and dyslexia.

CONTEXT. There is very little general evidence to support the clinical management, particularly diagnosis, of medically unexplained chronic pain (UCP) in children. OBJECTIVE. We sought to assess in children with UCP if clinical characteristics held important by general pediatricians help to accurately diagnose psychiatric morbidity and, alternatively, if the same can be achieved using dedicated questionnaires. METHODS. We used a cross-sectional diagnostic study in a pediatric outpatient clinic of a university hospital. Our participants were 134 patients, aged 8 to 18 years, who were referred for UCP. Performed were (1) diagnostic test reflecting the pediatricians’ choice of clinical characteristics and (2) selected questionnaires. Classification was performed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, by a child psychiatrist using the Diagnostic Interview Schedule for Children-Parent Version IV and the Semi-structured Clinical Interview for Children and Adolescents. Results were analyzed by logistic regression. RESULTS. Psychiatric morbidity was present in 80 of the children. A minority had a medical explanation for the pain (15% definite, 17% probable). The clinical diagnostic model included age, social-problem indicators, family structure, parental somatization, and school problems. In the quintile of children in whom this model predicted the highest risk, 93% indeed had psychiatric morbidity at reference testing. In the quintile with the lowest predicted risk, indeed only 27% had psychiatric morbidity. The Dutch Personality Inventory for Youth and the Child Behavior Checklist matched the pediatricians' choice of clinical characteristics. In the quintile of children with the highest predicted risk based on these questionnaires, 89% had psychiatric morbidity. In the quintile with the lowest predicted risk, only 15% had psychiatric morbidity. CONCLUSIONS. A pediatrician-chosen set of clinical characteristics of children with UCP proves useful in diagnosing psychiatric morbidity. Using selected questionnaire screening yields similar results.

The way glucocorticoids affect TRH mRNA expression in the paraventricular nucleus of the hypothalamus is still unclear. In view of its relevance for Cushing's syndrome and depression, we measured TRH mRNA expression in human hypothalami obtained at autopsy by means of quantitative TRH mRNA in situ hybridization. In corticosteroid-treated subjects ( n = 10), TRH mRNA hybridization signal was decreased as compared with matched control subjects ( n = 10) (Mann-Whitney U test, P = 0.02). By inference, hypercortisolism as present in patients with Cushing's syndrome or major depression may contribute to lower serum TSH or symptoms of depression by lowering hypothalamic TRH expression

It has been shown that peripheral injections of Olan induce Fos activation in neurons of the lateral hypothalamus/ perifornical area and that a large part of these activated neurons are Orexin A-positive (Stephanidis et al., 2009). In ongoing experiments we aim to confirm the involvement of the central Orexin system in the metabolic side-effects of Olan by comparing the hyperglycemic effects of IG Olan infusions between animals treated ICV with an Orexin A antagonist or Vehicle.

Publisher Summary Hypothalamo-pituitary adrenal (HPA)-axis hyperactivity leads to increased production of corticotrophin-releasing hormone (CRH) and cortisol; the central effects of these hormones form the final common pathway in the pathogenesis of symptoms of depression. HPAaxis activity may not only be caused by glucocorticoid receptor resistance, developmental sequelae or stress in adulthood, but also by stroke, especially if the left prefrontal cortex is affected. Transcranial cortical stimulation seems to be an effective new treatment for depression. HPA hyperactivity leads, in addition, to a decreased frontal metabolism, probably due to the inhibiting effect of glucocorticoids on the brain metabolism. The hyperactivity of the HPA axis may also explain at least part of the changes in the HPT-axis and contribute to decreased bioavailability of T3 in the brain. Hypofrontality and hyperactivity of the HPA-axis reinforce each other's actions in the development of the signs and symptoms of depression.

We describe a patient with thyrotoxic periodic paralysis (TPP) caused by a thyrotropin-secreting pituitary adenoma. The diagnosis TPP was based on the combination of episodes of reversible hypokalaemic paralysis, hyperthyroidism and electrophysiological findings. A thyrotropin-secreting pituitary adenoma was diagnosed on the basis of endocrinological function tests and MRI of the pituitary gland. Before transsphenoidal resection of the adenoma, treatment with octreotide restored euthyroidism both clinically and biochemically. Immunocytochemistry of the pituitary adenoma was positive for TSH exclusively. Incubation with octreotide or quinagolide induced decreased TSH and alpha-subunit production by the cultured adenoma cells, in agreement with the preoperative in vivo data. This paper is the first to describe in vivo and in vitro characteristics of a thyrotropin-secreting pituitary adenoma in a patient presenting with periodic paralysis. (J. Endocrinol. Invest. 21: 703-706, 1998) (C)1998, Editrice Kurtis.

Different nutrients are known to specifically alter glucose metabolism. When saturated fat and a sugar solution are consumed in addition to chow, rats become hyperphagic and insulin resistant. This is accompanied by an increase in Neuropeptide Y (NPY) in the arcuate nucleus (ARC) of the hypothalamus, a nucleus important for regulating glucose metabolism.

The case is described of a 40-year-old female with severe hypertension and hypokalaemic metabolic alkalosis, due to prolonged liquorice ingestion. The pseudo-aldosterone-like effects of liquorice have always been attributed to glycyrrhizic acid, but its biochemical substrate has remained elusive. It is now known that glycyrrhetenic acid, the hydrolytic metabolite of glycerrhizic acid, is the active component of liquorice which causes inhibition of the peripheral metabolism of cortisol. Cortisol binds with the same affinity as aldosterone to the mineralocorticoid receptor resulting in a hypermineralocorticoid condition. Ingestion of liquorice may therefore result in retention of sodium and water, hypertension, hypokalaemia, alkalosis and suppression of the renin-aldosterone system. The literature on liquorice-induced hypertension is briefly reviewed with emphasis on the biochemical features of this mineralocorticoid excess syndrome.

Volume and total cell number were determined in the supraoptic (SON) and paraventricular (PVN) nuclei of 14 male and 16 female subjects ranging in age from 10 to 93 years. In addition, 4 male and 6 female subjects suffering from Alzheimer's disease (AD) and ranging in age from 46 to 97 years were studied. Subjects were divided into two age groups, viz., "young" for subjects up to 60 years, and "old" for subjects older than 60. No sex differences in volume and in total cell number were observed in the SON and PVN in either age group. In addition, no significant correlation was found between total cell number in the SON and PVN and brain weight. No significant differences in volume and total cell number were found in either the SON or PVN between young and old control subjects or between AD cases and controls, indicating that these nuclei are spared from degenerative changes in senescence and AD. Determination of neuron numbers in the SON supported this view. In contrast, volume and total cell counts in the suprachiasmatic decreased in senescence and were dramatically reduced in AD. The present results indicate the occurrence of differential patterns of cell loss within the human hypothalamus with aging and in AD, which are proposed to be related to functional differences between the hypothalamic nuclei.

The neuropeptides vasopressin (AVP) and oxytocin (OXT) are supposed to be involved not only in peripheral functions (e.g. diuresis, labour and lactation) but also in central processes that are frequently disturbed during aging and senile dementia (e.g. fluid and electrolyte homeostasis and cognitive functions). A concomitant decrease in activity of the hypothalamo-neurohypophyseal system (HNS) with aging has been postulated in the literature, but has not yet been established. In order to investigate possible age-related changes in the human HNS, immunocytochemically identified AVP and OXT neurons in the paraventricular and supraoptic nucleus (PVN and SON) were analysed morphometrically in subjects from 10 to 93 years of age, including patients with senile dementia of the Alzheimer type (SDAT). Cell size was used as a parameter for peptide production. Mean profile area of OXT cells did not show any significant changes with increasing age. Mean profile area of AVP cells, however, showed an initial decrease up to the sixth decade of life, after which a gradual increase was observed. Size of AVP and OXT cell nuclei did not change significantly with aging. Observations in brains from patients with SDAT were within the range for their age group. The present results do not support degeneration or diminished function of the HNS in senescence of SDAT, as generally presumed in the literature, but suggest an activation of AVP cells after 80 years of age. The activation of AVP cells in senescence is in accordance with previous findings in the aged Wistar rat.

A recent study has shown that vasopressin (AVP) cells in the human supraoptic (SON) and paraventricular (PVN) nuclei increase in size after 60 years of age, suggesting that AVP production is increased in senescence. In the present study, the same brain material was used for the determination of nucleolar size in immunocytochemically identified AVP and oxytocin (OXT) neurons as an additional parameter for peptide production. A strong correlation was found between nucleolar size and cell size, both in AVP and OXT neurons. Nucleolar size of AVP but not of OXT neurons increased significantly in senescence. Observations in brains from patients with senile dementia of the Alzheimer type (SDAT) were commensurate with their ages. These results strongly support the hypothesis that AVP neurons in the SON and PVN are activated in old age.