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The non-thyroidal illness syndrome (NTIS) was first reported in the 1970s as a remarkable ensemble of changes in serum TH (TH) concentrations occurring in probably any severe illness. Ever since, NTIS has remained an intriguing phenomenon not only because of the robustness of the decrease in serum triiodothyronine (T3), but also by its clear correlation with morbidity and mortality. In recent years, it has become clear that (parenteral) feeding in patients with critical illness should be taken into account as a major determinant not only of NTIS but also of clinical outcome. Moreover, both experimental animal and clinical studies have shown that tissue TH concentrations during NTIS do not necessarily reflect serum low TH concentrations and may decrease, remain unaltered, or even increase according to the organ and type of illness studied. These differential changes now have a solid basis in molecular studies on organ-specific TH transporters, receptors and deiodinases. Finally, the role of inflammatory pathways in these non-systemic changes has begun to be clarified. A fascinating role for TH metabolism in innate immune cells, including neutrophils and monocytes/macrophages, was reported in recent years, but there is no evidence at this early stage that this may be a determinant of susceptibility to infections. Although endocrinologists have been tempted to correct NTIS by TH supplementation, there is at present insufficient evidence that this is beneficial. Thus, there is a clear need for adequately powered randomized clinical trials (RCT) with clinically relevant endpoints to fill this knowledge gap.

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.

BACKGROUND: Several human and rodent studies suggest that in addition to the amount of energy consumed, timing of food intake contributes to body weight regulation. Consuming most energy in the morning has favorable effects on weight loss and weight maintenance. Whether this also affects glucose metabolism and liver fat independently from weight loss is unknown. OBJECTIVE: We hypothesized that during weight loss, consuming most energy in the morning improves insulin sensitivity and reduces hepatic fat content more than consuming most energy in the evening. METHODS: Twenty-three obese insulin resistant men (age 59.9 +/- 7.9 years, body mass index 34.4 +/- 3.8 kg m(-2)) followed a 4-week hypocaloric diet intervention with either 50% of daily energy consumed in the morning (BF group) or evening (D group). Insulin sensitivity, measured with a two-step hyperinsulinemic euglycemic clamp using a glucose tracer, intrahepatic triglycerides (IHTG), measured using magnetic resonance spectroscopy, and resting energy expenditure (REE) were assessed before and after the diet intervention. RESULTS: Meal macronutrient composition and weight loss (6.5 +/- 1.5% vs 6.2 +/- 1.9%, respectively, P = 0.70) did not differ between the BF and D groups. Endogenous glucose production (P

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.

SummaryInhibition of sympathetic signaling to bone reduces bone resorption in rodents. In contrast, we show that pharmacological reduction of the sympathetic tone increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct pharmacological effect on the osteoclast.IntroductionInhibition of sympathetic signaling to bone reduces bone resorption in rodents. It is uncertain whether a similar role for the sympathetic nervous system exists in humans. The sympathetic tone can be reduced by clonidine, which acts via alpha-2-adrenergic receptors in the brainstem. Our objective was to determine the effect of clonidine on bone turnover in humans.MethodsThe acute effect of a single oral dose of 0.3 mg clonidine on serum bone turnover markers (C-terminal cross-linking telopeptides of collagen type I (CTx), a marker for bone resorption, and procollagen type 1 N propeptide (P1NP), a marker for bone formation) was determined in a randomized crossover design in 12 healthy volunteers, aged 18–70 years. In addition, we assessed the effect of clonidine on the number of tartrate-resistant acid phosphatase–positive multinucleated cells (TRAcP+ MNCs) and bone resorption.ResultsCTx concentrations increased after clonidine treatment compared to the control condition (p = 0.035). P1NP concentrations were not affected by clonidine (p = 0.520).In vitro, clonidine had no effect on the number of TRAcP+ MNCs (p = 0.513) or on bone resorption (p = 0.996).ConclusionsWe demonstrated that clonidine increases bone resorption in humans in vivo. This effect does not appear to be mediated via a direct effect on the osteoclast.

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

Purpose: Genetic knockout or pharmacological inhibition of the beta-2 adrenergic receptor (B2AR) increased bone mass, whereas stimulation decreased bone mass in rodents. In humans, observational studies support sympathetic nervous system regulation of bone metabolism, but intervention studies are lacking. We aimed to determine the effects of a selective beta-2 adrenergic agonist and non-selective antagonist on human bone metabolism. Methods: 32 healthy postmenopausal women were included in a randomized controlled trial conducted in the Academic Medical Center Amsterdam. Participants were randomized to receive treatment with 17-β estradiol 2. mg/day; 17-β estradiol 2. mg/day and terbutaline 5. mg/day (selective B2AR agonist); propranolol 80. mg/day (non-selective B-AR antagonist); or no treatment during 12. weeks. Main outcome measure was the change in serum concentrations of procollagen type I N propeptide (P1NP) and C-terminal crosslinking telopeptides of collagen type I (CTx) as markers of bone formation and resorption after 12. weeks compared between the treatment groups. Data were analyzed with mixed model analysis. Results: 17-β estradiol decreased bone turnover compared to control (P1NP p.

The brain is well known to regulate blood glucose, and the hypothalamus and hindbrain, in particular, have been studied extensively to understand the underlying mechanisms. Nuclei in these regions respond to alterations in blood glucose concentrations and can alter glucose liver output or glucose tissue uptake to maintain blood glucose concentrations within strict boundaries. Interestingly, several cortico-limbic regions also respond to alterations in glucose concentrations and have been shown to project to hypothalamic nuclei and glucoregulatory organs. For instance, electrical stimulation of the shell of the nucleus accumbens (sNAc) results in increased circulating concentrations of glucose and glucagon and activation of the lateral hypothalamus (LH). Whether this is caused by the simultaneous increase in serotonin release in the sNAc remains to be determined. To study the effect of sNAc serotonin on systemic glucose metabolism, we implanted bilateral microdialysis probes in the sNAc of male Wistar rats and infused fluoxetine, a serotonin reuptake inhibitor, or vehicle after which blood glucose, endogenous glucose production (EGP) and glucoregulatory hormones were measured. Fluoxetine in the sNAc for 1h significantly increased blood glucose concentrations without an effect on glucoregulatory hormones. This increase was accompanied by a higher EGP in the fluoxetine infused rats compared to the controls. These data provide further evidence for a role of sNAc-serotonin in the regulation of glucose metabolism.

Deiodinase type 2 (D2) is a thyroid hormone-activating enzyme converting the prohormone T-4 into the active hormone T-3. In the present study, we show for the first time that D2 is up-regulated in the mouse liver during acute and chronic inflammation, in close correlation with the proinflammatory cytokine IL-1 beta and independently of serum T-3. Inflammation-induced D2 expression was confirmed in macrophages, in conjunction with selective thyroid hormone transporter (monocarboxylate transporter 10) and thyroid hormone receptor (TR)alpha 1 stimulation, and was absent in hepatocytes. Moreover, D2 knockdown in macrophages resulted in a clear attenuation of the lipopolysaccharide (LPS)-induced IL-1 beta and GM-CSF expression, in addition to aberrant phagocytosis. Locally produced T-3, acting via the TR alpha, may be instrumental in this novel inflammatory response, because LPS-treated TR alpha(0/0) mice showed a markedly decreased LPS-induced GM-CSF mRNA expression. We now propose that hepatic D2 favors the innate immune response by specifically regulating cellular thyroid hormone levels in macrophages

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.

The enzyme type 2 deiodinase (D2) is a major determinant of T3 production in the central nervous system. It is highly expressed in tanycytes, a specialized cell type lining the wall of the third ventricle. During acute inflammation, the expression of D2 in tanycytes is up-regulated by a mechanism that is poorly understood at present, but we hypothesized that cJun N-terminal kinase 1 (JNK1) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) (the 65 kD subunit of NFκB) inflammatory signal transduction pathways are involved. In a mouse model for acute inflammation, we studied the effects of lipopolysaccharide (LPS) on mRNA expression of D2, JNK1, and RelA in the periventricular area (PE) and the arcuate nucleus-median eminence of the hypothalamus. We next investigated LPS-induced D2 expression in primary tanycyte cell cultures. In the PE, the expression of D2 was increased by LPS. In the arcuate nucleus, but not in the PE, we found increased RelA mRNA expression. Likewise, LPS increased D2 and RelA mRNA expression in primary tanycyte cell cultures, whereas JNK1 mRNA expression did not change. Phosphorylation of RelA and JNK1 was increased in tanycyte cell cultures 15–60 minutes after LPS stimulation, confirming activation of these pathways. Finally, inhibition of RelA with the chemical inhibitors sulfasalazine and 4-Methyl-N1-(3-phenylpropyl)benzene-1,2-diamine (JSH-23) in tanycyte cell cultures prevented the LPS-induced D2 increase. We conclude that NFκB signaling is essential for the up-regulation of D2 in tanycytes during inflammation.

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.

ObjectiveRadioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients.DesignRetrospective multicenter study in eight University Medical Centers in The Netherlands.MethodsTwo hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease.ResultsIn multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification.ConclusionsBased on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

A large proportion of critically ill patients have alterations in the hypothalamus-pituitary-thyroid (HPT) axis, collectively known as the nonthyroidal illness syndrome. Nonthyroidal illness syndrome is characterized by low serum thyroid hormone (TH) concentrations accompanied by a suppressed central component of the HPT axis and persistent low serum TSH. In hypothalamic tanycytes, the expression of type 2 deiodinase (D2) is increased in several animal models of inflammation. Because D2 is a major source of T3 in the brain, this response is thought to suppress TRH expression in the paraventricular nucleus via increased local bioavailability of T3. The inflammatory pathway component RelA (the p65 subunit of nuclear factor-κB) can bind the Dio2 promoter and increases D2 expression after lipopolysaccharide (LPS) stimulation in vitro. We aimed to determine whether RelA signaling in tanycytes is essential for the LPS-induced D2 increase in vivo by conditional elimination of RelA in tanycytes of mice (RelAASTKO). Dio2 and Trh mRNA expression were assessed by quantitative in situ hybridization 8 or 24 hours after saline or LPS injection. At the same time points, we measured pituitary Tshβ mRNA expression and serum T3 and T4 concentrations. In RelAASTKO mice the LPS-induced increase in Dio2 and decrease in Trh mRNA levels in the hypothalamus were reduced compared with the wild-type littermates, whereas the drop in pituitary Tshβ expression and in serum TH concentrations persisted. In conclusion, RelA is essential for the LPS-induced hypothalamic D2 increase and TRH decrease. The central changes in the HPT axis are, however, not required for the down-regulation of Tshβ expression and serum TH concentrations.

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.

Estrogen deficiency after ovariectomy (OVX) results in increased adiposity and bone loss, which can be prevented by systemic 17-beta estradiol (E2) replacement. Studies in transgenic mice suggested that in addition to direct actions of estrogen in peripheral tissues, also estrogen signaling in the hypothalamus regulates fat distribution and bone metabolism. We hypothesized that the protective effect of systemic E2 on fat and bone metabolism in the OVX model is partly mediated through the ventromedial nucleus of the hypothalamus (VMH). To test this hypothesis, we determined the effect of systemic, central, and targeted VMH administration of E2 on fat and bone metabolism in OVX rats. Subcutaneous administration of E2 for 4 weeks decreased body weight, gonadal and perirenal fat, and bone formation rate in OVX rats. This effect was completely mimicked by intracerebroventricular injections of E2, once every 4 days for 4 weeks. Administration of E2 locally in the VMH by retromicrodialysis (3 h) acutely increased expression of the lipolytic gene hormone-sensitive lipase in gonadal and perirenal fat. Finally, chronic administration of E2 in the VMH for 8 weeks decreased perirenal fat but did not affect body weight, trabecular bone volume, or cortical thickness. In conclusion, we demonstrated that intracerebroventricular E2 replacement reduces body weight gain, ameliorates intraabdominal fat accumulation, and reduces bone formation in the OVX rats. E2 administration selectively in the VMH also reduced intraabdominal fat but did not affect bone metabolism.

The pronounced daily variation in the release of adrenal hormones has been at the heart of the deciphering and understanding of the circadian timing system. Indeed, the first demonstration of an endocrine day/night rhythm was provided by Pincus (1943), by showing a daily pattern of 17-keto-steroid excretion in the urine of 7 healthy males. Twenty years later the adrenal gland was one of the very first organs to show, in vitro, that circadian rhythmicity was maintained. In the seventies, experimental manipulation of the daily corticosterone rhythm served as evidence for the identification of respectively the light- and food-entrainable oscillator. Another 20 years later the hypothalamo-pituitary-adrenal (HPA)-axis was key in furthering our understanding of the way in which rhythmic signals generated by the central pacemaker in the hypothalamic suprachiasmatic nuclei (SCN) are forwarded to the rest of the brain and to the organism as a whole. To date, the adrenal gland is still of prime importance for understanding how the oscillations of clock genes in peripheral tissues result in functional rhythms of these tissues, whereas it has become even more evident that adrenal glucocorticoids are key in the resetting of the circadian system after a phase-shift. The HPA-axis thus still is an excellent model for studying the transmission of circadian information in the body. (C) 2011 Elsevier Ireland Ltd. All rights reserved

Background Awakening from sleep is a clear example of an event for which the biological clock is of great importance. We will review some major pathways the mammalian biological clock uses to ensure an efficient and coordinated wake-up process.

The biological function of thyrostimulin, consisting of the GPA2 and GPB5 subunit, is currently poorly understood. The recent observation that pro-inflammatory cytokines up-regulate the transcription of GPB5 in vitro suggested a role for thyrostimulin in the nonthyroidal illness syndrome, a state of altered thyroid hormone metabolism occurring during illness. In the present study, we used GPB5 knockout (GPB5 ―/― ) and wild-type (WT) mice to evaluate the role of GPB5 in the pituitary and hypothalamus during acute inflammation induced by lipopolysaccharide (LPS, bacterial endotoxin) administration. We evaluated serum thyroid hormones and mRNA expression of genes involved in thyroid hormone metabolism in the pituitary and in two hypothalamic regions; the periventricular region (PE) and the arcuate nucleus/median eminence region. As expected, LPS administration increased deiodinase type 2 mRNA in the PE, at the same time as decreasing pituitary thyrotrophin (TSH)β mRNA and serum thyroxine and triiodothyronine both in GPB5 ―/― and WT mice. GPB5 mRNA, but not GPA2 mRNA, markedly increased after LPS in the pituitary (200-fold) and hypothalamus of WT mice. In addition, we found large (> 50%) suppression of TSH receptor (TSHR) mRNA in the pituitary and hypothalamus of WT mice but not in GPB5 ―/― mice. In conclusion, our results demonstrate in vivo regulation of central GPB5 transcription during acute illness. The observed differences between GPB5 ―/― and WT mice point to a distinct role for GPB5 in pituitary and hypothalamic TSHR suppression during acute illness.

The hypothalamic control of hepatic glucose production is an evident aspect of energy homeostasis. In addition to the control of glucose metabolism by the circadian timing system, the hypothalamus also serves as a key relay center for (humoral) feedback information from the periphery, with the important role for hypothalamic leptin receptors as a striking example. The hypothalamic biological clock uses its projections to the preautonomic hypothalamic neurons to control the daily rhythms in plasma glucose concentration, glucose uptake, and insulin sensitivity. Euglycemic, hyperinsulinemic clamp experiments combined with either sympathetic-, parasympathetic-, or sham-denervations of the autonomic input to the liver have further delineated the hypothalamic pathways that mediate the control of the circadian timing system over glucose metabolism. In addition, these experiments clearly showed both that next to the biological clock peripheral hormones may "use" the preautonomic neurons in the hypothalamus to affect hepatic glucose metabolism, and that similar pathways may be involved in the control of lipid metabolism in liver and white adipose tissue.

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 : 69105.pdf (Publisher’s version ) (Closed access) Meta-analyses indicate that the gene coding for the dopamine transporter (DAT1 or SLC6A3) is associated with an increased risk for ADHD. The mechanisms of this gene for ADHD are unclear. We systematically reviewed studies linking the VNTR in the 3' UTR of the DAT1 to neurophysiological and neuropsychological measures. In addition, a broad set of executive/cognitive and motor tests was administered to 350 children (5-11 years) and adolescents (11-19 years) with ADHD and 195 non-affected siblings. Two VNTRs (in intron 8 and the 3' UTR) and four SNPs (two 5' and two 3') in DAT1 were genotyped. The effect of the polymorphisms on neuropsychological functioning was studied. The review indicated that the majority of studies did not find a relation between DAT1 and neurophysiological or neuropsychological measures. In our sample, several of the polymorphisms of DAT1 were associated with ADHD and ADHD was associated with impaired neuropsychological functioning. However, none of the DAT1 polymorphisms was convincingly associated with neuropsychological dysfunctioning. This suggests that the effect of DAT1 on ADHD was not mediated by neuropsychological performance. However, since DAT1 is mainly expressed in the striatum and not the prefrontal cortex, it may influence striatum-related functions (such as delay aversion) more heavily than prefrontal related functions (such as executive functions). Associations of DAT1 with ADHD were only found in adolescents, which may suggest that DAT1 mainly exerts its effect in adolescence, and/or that having a more persistent form of ADHD may mark a more severe or homogeneous genetic form of the disorder.

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.

Context: Increased plasma free fatty acid (FFA) concentrations may be in part responsible for the increased levels of ceramide in skeletal muscle of obese subjects.Objective: We studied the effect of lowering and increasing plasma FFA levels on muscle ceramide and glucosylceramide concentrations in lean and obese subjects.Design: Plasma FFAs were either increased or decreased for 6 h by infusing a lipid emulsion or using Acipimox, respectively. Muscle biopsies were performed before and after the intervention for measurements of ceramide and glucosylceramide.Study Subjects: Eight lean [body mass index 21.9 (range, 19.6–24.6) kg/m2] and six overweight/obese [body mass index 34.4 (27.8–42.5) kg/m2] subjects without type 2 diabetes mellitus participated in the study.Main Outcome Measure: Differences in muscle ceramide and glucosylceramide upon manipulation of plasma FFAs were measured.Results: There were no differences in muscle ceramide and glucosylceramide between lean and obese subjects, respectively. Increasing or decreasing plasma FFAs for 6 h had no effect on ceramide [high FFAs: 24 (19–25) vs. 24 (22–27) pmol/mg muscle, P = 0.46; and 22 (20–28) vs. 24 (18–26) pmol/mg muscle, P = 0.89 in lean and obese, respectively; low FFAs: 26 (24–35) vs. 23 (18–27) pmol/mg muscle, P = 0.17 and 24 (15–44) vs. 24 (19–42) pmol/mg muscle, P = 0.6 in lean and obese, respectively] and glucosylceramide [high FFAs: 2.0 (1.7–4.3) vs. 3.4 (2.1–4.6) pmol/mg muscle, P = 0.17; and 3.0 (1.3–6.7) vs. 2.6 (1.2–3.9) pmol/mg muscle, P = 0.89 in lean and obese, respectively; low FFAs: 2.2 (1.0–4.4) vs. 1.7 (1.4–3.0) pmol/mg muscle, P = 0.92; and 6.6 (1.0–25.0) vs. 4.3 (1.3–7.6) pmol/mg muscle, P = 0.7 in lean and obese, respectively] concentrations in skeletal muscle.Conclusion: Short-term manipulation of plasma FFAs has no effect on ceramide and glucosylceramide concentrations in skeletal muscle from lean and obese subjects.

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.

During illness, changes in thyroid hormone metabolism occur, known as nonthyroidal illness and characterised by decreased serum triiodothyronine (T3) and thyroxine (T4) without an increase in TSH. A mouse model of chronic illness is local inflammation, induced by a turpentine injection in each hind limb. Although serum T3 and T4 are markedly decreased in this model, it is unknown whether turpentine administration affects the central part of the hypothalamus–pituitary–thyroid axis (HPT-axis). We therefore studied thyroid hormone metabolism in hypothalamus and pituitary of mice during chronic inflammation induced by turpentine injection. Using pair-fed controls, we could differentiate between the effects of chronic inflammation per se and the effects of restricted food intake as a result of illness. Chronic inflammation increased interleukin (IL)-1β mRNA expression in the hypothalamus more rapidly than in the pituitary. This hypothalamic cytokine response was associated with a rapid increase in local D2 mRNA expression. By contrast, no changes were present in pituitary D2 expression. TSHβ mRNA expression was altered compared with controls. Comparing chronic inflamed mice with pair-fed controls, both preproTSH releasing hormone (TRH) and D3 mRNA expression in the paraventricular nucleus were significantly lower 48 h after turpentine administration. The timecourse of TSHβ mRNA expression was completely different in inflamed mice compared with pair-fed mice. Turpentine administration resulted in significantly decreased TSHβ mRNA expression only after 24 h while later in time it was lower in pair-fed controls. In conclusion, central thyroid hormone metabolism is altered during chronic inflammation and this cannot solely be attributed to diminished food intake.

Profound changes in thyroid hormone metabolism occur in the central part of the hypothalamus–pituitary–thyroid (HPT) axis during fasting. Hypothalamic changes are partly reversed by leptin administration, which decreases during fasting. It is unknown to what extent leptin affects the HPT axis at the level of the pituitary. We, therefore, studied fasting-induced alterations in pituitary thyroid hormone metabolism, as well as effects of leptin administration on these changes. Because refeeding rapidly increased serum leptin, the same parameters were studied after fasting followed by refeeding. Fasting for 24 h decreased serum T3 and T4 and pituitary TSHβ, type 2deiodinase (D2), and thyroid hormone receptor β2 (TRβ2) mRNA expression. The decrease in D2 and TRβ2 mRNA expression was prevented when 20 μg leptin was administered twice during fasting. By contrast, the decrease in TSHβ mRNA expression was unaffected. A single dose of leptin given after 24 h fasting did not affect decreased TSHβ, D2, and TRβ2 mRNA expression, while 4 h refeeding resulted in pituitary D2 and TRβ2 mRNA expression as observed in control mice. Serum leptin, T3, and T4 after refeeding were similar compared with leptin administration. We conclude that fasting decreases pituitary TSHβ, D2, and TRβ2 mRNA expression, which (with the exception of TSHβ) can be prevented by leptin administration during fasting. Following 24 h fasting, 4 h refeeding completely restores pituitary D2 and TRβ2 mRNA expression, while a single leptin dose is ineffective. This indicates that other postingestion signals may be necessary to modulate rapidly the fasting-induced decrease in pituitary D2 and TRβ2 mRNA expression.

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.

Previous studies have shown a diurnal variation of certain isoforms of thyroid hormone receptors (TR) in rat liver. The genesis of these diurnal changes is still unknown. To clarify whether the biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), is involved, we made selective SCN lesions. Rats with an SCN lesion lost their circadian rhythm of plasma corticosterone and TSH when compared with intact animals. TRα1 and TRα2 mRNA expression of control rats was higher in the light period than in the dark period; changes that were abolished in the rats with SCN lesions. In contrast, liver TRβ1 mRNA of intact rats showed a diurnal variation that failed to reach statistical significance. To evaluate whether these effects could be explained indirectly by the disappearance of rhythmic feeding behavior in rats with SCN lesions, we performed a second experiment in which otherwise intact animals were subjected to a regular feeding (RF) schedule, with one meal every 4 h. When compared with rats with free access to food, RF only affected TRβ1 mRNA expression and had no effect on the diurnal changes in TRα1 and TRα2. We conclude that liver TRβ1 expression is most clearly affected by food intake. Diurnal changes in liver TRα1 and TRα2 are controlled by the biological clock in the SCN but not via changes in the daily rhythm of food intake. The findings may have physiological relevance for diurnal variation of T3-dependent gene expression, which is supported by a diurnal variation in the expression of the 5′-deiodinase gene.

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.

During fasting, profound changes in the regulation of the hypothalamus-pituitary-thyroid axis occur in order to save energy and limit catabolism. In this setting, serum T3 and T4 are decreased without an appropriate TSH and TRH response reflecting central down-regulation of the hypothalamus-pituitary-thyroid axis. Hepatic thyroid hormone (TH) metabolism is also affected by fasting, because type 3 deiodinase (D3) is increased, which is mediated by serum leptin concentrations. A recent study showed that fasting-induced changes in liver TH sulfotransferases (Sults) and uridine 5′-diphospho-glucuronosyltransferase (Ugts) depend on a functional melanocortin system in the hypothalamus. However, the pathways connecting the hypothalamus and the liver that induce these changes are currently unknown. In the present study, we investigated in rats whether the fasting-induced changes in hepatic TH metabolism are regulated by the autonomic nervous system. We selectively cut either the sympathetic or the parasympathetic input to the liver. Serum and liver TH concentrations, deiodinase expression, and activity and Sult and Ugt expression were measured in rats that had been fasted for 36 hours or were fed ad libitum. Fasting decreased serum T3 and T4 concentrations, whereas intrahepatic TH concentrations remained unchanged. D3 expression and activity increased, as was the expression of constitutive androstane receptor, Sult1b1, and Ugt1a1, whereas liver D1 was unaffected. Neither sympathetic nor parasympathetic denervation affected the fasting-induced alterations. We conclude that fasting-induced changes in liver TH metabolism are not regulated via the hepatic autonomic input in a major way and more likely reflect a direct effect of humoral factors on the hepatocyte.

The hypothalamus is the most prominent brain region involved in setpoint regulation of the thyroid axis. It generates the diurnal thyroid-stimulating hormone (TSH) rhythm, and it plays a central role in the adaptation of the thyroid axis to environmental factors such as caloric deprivation or infection. Many studies, including studies in human post-mortem tissue samples, have confirmed a key role for the thyrotropin-releasing hormone (TRH) neuron in the hypothalamic paraventricular nucleus (PVN) in thyroid axis regulation. In addition to their negative feedback action on TRH neurons in the hypothalamus, intrahypothalamic thyroid hormones can also modulate metabolism in adipose tissue and the liver via the autonomic nervous system. Congenital or acquired dysfunction of the hypothalamus or pituitary gland may result in central hypothyroidism (CeH). In the Netherlands, the prevalence of permanent congenital CeH as detected by neonatal screening is approximately 1 in 18000. In most neonates congenital CeH is accompanied by additional anterior pituitary hormone deficiencies, and many show clear morphological abnormalities such as a small anterior gland, a thin or absent pituitary stalk, or an ectopic posterior pituitary gland. Recently, a mutation in the immunoglobulin superfamily member 1 (IGSF1) gene was reported as a novel cause of X-linked, apparently isolated CeH occurring in neonates, children and adults. In adults, the most frequent cause of acquired CeH is a pituitary macroadenoma, usually accompanied by other pituitary hormone deficiencies. Central hyperthyroidism is a rare disorder, especially in children. In adults, it is mostly caused by a TSH-secreting pituitary adenoma.

At present it is not clear which factors are responsible for the diurnal pattern of plasma leptin levels, although the timing of food intake and circulating hormones such as glucocorticoids and insulin have both been proposed as independent determinants. In this study we show that ablation of the biological clock by thermal lesions of the hypothalamic suprachiasmatic nucleus (SCN) completely eliminates the diurnal pattern of plasma leptin levels. By contrast, removal of the diurnal corticosterone signal by adrenalectomy and corticosterone replacement did not affect diurnal plasma leptin levels. More importantly, removal of the nocturnal feeding signal by submitting the animals to a regular feeding schedule of six meals per day did not abolish the diurnal plasma leptin levels. However, both SCN lesions and the regular feeding schedule did cause an increase in the 24-h mean plasma leptin levels. As neither rhythmic feeding, insulin, or corticosterone signals can completely explain the diurnal plasma leptin rhythm, we conclude that biological clock control of the sympathetic input to the adipocyte is essential for regulation of the daily rhythm in leptin release.

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

Sinds het begin van de evolutie zijn bijna alle wezens op aarde onderworpen aan het dagelijkse ritme van licht en donker. Als gevolg hiervan ervaren de meeste levende wezens ook een dagelijks ritme in de aanwezigheid van voedsel. In dit artikel beschrijven we de biologische klok, bestaande uit een centrale klok in de nucleus suprachiasmaticus (SCN) en perifere klokken in verschillende weefsels (waaronder de lever, de alvleesklier en de darm).We beschrijven hoe de perifere klokken aangestuurd worden door de centrale klok en door metabole signalen. Vervolgens gaan we in op de invloed van de biologische klok op voedselinname, activiteit van het gastro-intestinale systeem en de stofwisseling van glucose en lipiden. Daarna beschrijven we de gevolgen van de invloed van de biologische klok op de spijsvertering en de stofwisseling, waarbij we ingaan op de gezondheidseffecten van het tijdstip van voedselinname, de maaltijdfrequentie en al dan niet ontbijten. Ook gaan we in op de mogelijke consequenties van de aanwezigheid van de biologische klok voor het toedieningsschema van sondevoeding en parenterale voeding. Ten slotte beschrijven we de relatie tussen de biologische klok en diabetes mellitus type 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

Estrogen plays an important role in the regulation of the hypothalamus-pituitary-adrenal (HPA)-axis,but the neuroendocrine pathways and the role of estrogen receptor (ER) subtypes involved in specific aspects of this interaction remain unknown. In a first set of experiments, we administered estradiol (E2) intravenously, intracerebroventricularly, and by intrahypothalamic microdialysis to ovariectomized rats to measure plasma corticosterone (CORT) concentrations from carotid artery blood. Systemic infusion of E2 did not increase plasma CORT, but intracerebroventricular E2 induced a 3-fold CORT increase (P = 0.012). Local E2 infusions in the hypothalamic paraventricular nucleus (PVN) significantly increased plasma CORT (P

Children with attention deficit hyperactivity disorder (ADHD) do not only display hyperactive motor behaviour, but half of them are also clumsy when executing motor skills. Alongside displaying hyperactivity and poor concentration skills, they have difficulty with writing, tying shoelaces, eating properly using fork and knife, and playing games and sports. This is known as dyspraxia or developmental coordination disorder (DCD). Poor performance in sports and games is, just as ADHD, an important negative predictor of a child's popularity within the peer group. Children with a combination of ADHD and poor motor performance are doubly disadvantaged. A dopamine-induced imbalance in the neuronal circuits of the basal ganglia and the cerebellum is a possible cause of ADHD-DCD. On the basis of family and twin studies, there are also indications that ADHD and DCD have a common genetic background. In daily practice, DCD receives too little attention during diagnosis and treatment of ADHD. Screening for motor problems in children with ADHD, followed by referral to a physiotherapist or occupational therapist if necessary, is useful, because treatment with cognitive-oriented and task-oriented physiotherapy can help.

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.