[Child psychiatric learning goals for general psychiatric training: a Delphi study]. / Leerdoelen over kinder- en jeugdpsychiatrie in de opleiding psychiatrie: een delphistudie.

BACKGROUND: The new Dutch training plan for psychiatrists puts more emphasis on life course psychiatry. Subsequently, adjustments in the educational program regarding child and adolescent psychiatric knowledge, skills and attitudes are needed. AIM: A broadly supported agreement and consensus on Dutch national learning objectives of education in child and adolescent psychiatry. METHOD: With a modified Delphi method, a set of preliminary learning objectives formulated by a working group of experts was presented to trainees (n = 9), adult psychiatrists (n = 12), child and adolescent psychiatrists (n = 17) and adult patients and their relatives (n = 15). In two rounds, the learning objectives were commented on, supplemented, scored for relevance and prioritized. RESULTS: Out of 27 original learning objectives, 20 were assessed as important or necessary by over 80% of the respondents (knowledge 7/9, skills 8/10, attitudes 5/8). Two learning objectives were rejected (less than 60% considered these to be important or necessary). Seven learning objectives were re-assessed in a second round as these were modified (5) or added (2). Four of them were rated as important or necessary by over 80% of participants. The following goals were most often prioritized: knowledge about healthy development and intergenerational issues; ability to make contact with children and families and to integrate protective and risk factors of the child and environment; and knowing one’s own limitations of child psychiatric themes. CONCLUSION: A Delphi study helped gain support from stakeholders for adjustments in training and education by creating consensus about child psychiatric learning goals for general psychiatric training.

Catecholaminergic and cholinergic neuromodulation in autism spectrum disorder: A comparison to attention-deficit hyperactivity disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by social impairments and restricted, repetitive behaviors. Treatment of ASD is notoriously difficult and might benefit from identification of underlying mechanisms that overlap with those disturbed in other developmental disorders, for which treatment options are more obvious. One example of the latter is attention-deficit hyperactivity disorder (ADHD), given the efficacy of especially stimulants in treatment of ADHD. Deficiencies in catecholaminergic systems [dopamine (DA), norepinephrine (NE)] in ADHD are obvious targets for stimulant treatment. Recent findings suggest that dysfunction in catecholaminergic systems may also be a factor in at least a subgroup of ASD. In this review we scrutinize the evidence for catecholaminergic mechanisms underlying ASD symptoms, and also include in this analysis a third classic ascending arousing system, the acetylcholinergic (ACh) network. We complement this with a comprehensive review of DA-, NE-, and ACh-targeted interventions in ASD, and an exploratory search for potential treatment-response predictors (biomarkers) in ASD, genetically or otherwise. Based on this review and analysis we propose that (1) stimulant treatment may be a viable option for an ASD subcategory, possibly defined by genetic subtyping; (2) cerebellar dysfunction is pronounced for a relatively small ADHD subgroup but much more common in ASD and in both cases may point toward NE- or ACh-directed intervention; (3) deficiency of the cortical salience network is sizable in subgroups of both disorders, and biomarkers such as eye blink rate and pupillometric data may predict the efficacy of targeting this underlying deficiency via DA, NE, or ACh in both ASD and ADHD.

Lead, zinc, and copper redistributions in soils along a deposition gradient from emissions of a Pb-Ag smelter decommissioned 100 years ago.

Sourcing and understanding the fate of anthropogenic metals in a historical contamination context is challenging. Here we combined elemental and isotopic (Pb, Zn, Cu) analyses with X-ray Absorption Spectroscopy (XAS) measurements (Zn) to trace the fate, in undisturbed soil profiles, of historical metal contamination emitted by a 167-year-old Pb-Ag smelter decommissioned 100 years ago located in the Calanques National Park (Marseilles, France). Lead isotopic measurements show that entire soil profiles were affected by 74 years of Pb emissions up to ~7 km from the smelter under the main NNW wind, and indicate particulate transfer down to 0.8 m at depth. This vertical mobility of anthropogenic Pb contrasts with previous studies where Pb was immobilized in surface horizons. The contribution of anthropogenic Pb to the total Pb concentration in soil was estimated at 95% in surface horizons, and 78% in the deepest horizons. Zinc isotopic signatures of past emissions that are enriched in light isotopes compared to the natural geological background (-0.70 ±â€¯0.04‰ and -0.15 ±â€¯0.02‰, respectively), were detected only in the surface horizons of the studied soils. Using XAS analyses, we showed that anthropogenic Zn was transformed and immobilized in surface horizons as Zn-Layered Double Hydroxide, thus favoring the enrichment in heavy isotopes in these surface horizons. No clear evidence of copper contamination by the smelter was found and Cu isotopes point to a bedrock origin and a natural distribution of Cu concentrations.

Crystal structure of the active form of native human thymidylate synthase in the absence of bound substrates.

Human thymidylate synthase (hTS) provides the sole de novo intracellular source of thymidine 5'-monophosphate (dTMP). hTS is required for DNA replication prior to cell division, making it an attractive target for anticancer chemotherapy and drug discovery. hTS binds 2'-deoxyuridine 5'-monophosphate (dUMP) and the folate co-substrate N5,N10-methylenetetrahydrofolate (meTHF) in a pocket near the catalytic residue Cys195. The catalytic loop, which is composed of amino-acid residues 181-197, can adopt two distinct conformations related by a 180° rotation. In the active conformation Cys195 is close to the active site, while in the inactive conformation it is rotated and Cys195 is too distant from the active site for catalysis. Several hTS structures, either native or engineered, have been solved in the active conformation in complex with ligands or inhibitors and at different salt concentrations. However, apo hTS structures have been solved in an inactive conformation in high-salt and low-salt conditions (PDB entries 1ypv, 4h1i, 4gyh, 3egy and 3ehi). Here, the structure of apo hTS crystallized in the active form with sulfate ions coordinated by the arginine residue that binds dUMP is reported.

Empathy and prosocial behavior in response to sadness and distress in 6- to 7-year olds diagnosed with disruptive behavior disorder and attention-deficit hyperactivity disorder.

Empathy has been associated with decreased antisocial and increased prosocial behavior. This study examined empathy and prosocial behavior in response to sadness and distress in disruptive behavior disorder (DBD) and attention-deficit hyperactivity disorder (ADHD). Six- and 7-year-old children with DBD (with and without ADHD) (n = 67) and with ADHD only (n = 27) were compared to typically developing children (TD) (n = 37). Parents and teachers rated affective empathy in response to sadness and distress on the Griffith Empathy Measure. Children reported affective empathic ability in response to sad story vignettes. Empathy-induced prosocial behavior in response to sadness and distress was assessed with a computer task, the Interpersonal Response Task (IRT). Compared to TD, children with DBD (with and without ADHD) and those with ADHD only were rated as less empathic by their teachers, but not by their parents. No differences between groups were observed in children who reported affect correspondence. Children with DBD (with and without ADHD) showed less prosocial behavior in response to sadness and distress compared to TD. Children with ADHD only did not differ from TD. An additional analysis comparing all children with a diagnosis to the TD group revealed that the difference in prosocial behavior remained after controlling for ADHD symptoms, but not after controlling for DBD symptoms. These findings of impaired empathy-induced prosocial behavior in response to sadness and distress in young children with DBD suggest that interventions to ameliorate peer relationships may benefit from targeting on increasing prosocial behavior in these children.

Electromyographic responses to emotional facial expressions in 6-7 year olds with autism spectrum disorders.

This study aimed to examine facial mimicry in 6-7 year old children with autism spectrum disorder (ASD) and to explore whether facial mimicry was related to the severity of impairment in social responsiveness. Facial electromyographic activity in response to angry, fearful, sad and happy facial expressions was recorded in twenty 6-7 year old children with ASD and twenty-seven typically developing children. Even though results did not show differences in facial mimicry between children with ASD and typically developing children, impairment in social responsiveness was significantly associated with reduced fear mimicry in children with ASD. These findings demonstrate normal mimicry in children with ASD as compared to healthy controls, but that in children with ASD the degree of impairments in social responsiveness may be associated with reduced sensitivity to distress signals.

Differences between nicotine-abstinent smokers and non-smokers in terms of visuospatial attention and inhibition before and after single-blind nicotine administration.

The cholinergic system is implicated in visuospatial attention and inhibition, however the exact role is still unclear. Two key mechanisms in visuospatial attention are bias and disengagement. Bias refers to neuronal signals that enhance the sensitivity of the sensory cortex, disengagement is the decoupling of attention. Previous studies suggest that nicotine affects disengagement and (related) inhibition. However the exact relation is still unknown. Furthermore, nicotine-abstinence in 'healthy' smokers may resemble some anomalies of visuospatial attention and inhibition as seen in Attention Deficit/Hyperactivity Disorder (ADHD). Smokers and non-smokers (32 male students) performed in a visuospatial cueing (VSC) task, to assess bias and disengagement, and in a stop-signal task (SST) to assess inhibition. It was expected that nicotine abstinent smokers compared to non-smokers, would show poor disengagement (indicated by an enhanced validity effect) and poor inhibitory control (indicated by an enhanced stop-signal reaction time (SSRT)). It was expected that nicotine would positively affect disengagement and inhibition: hypothesis 1 stated that this effect would be larger in smokers as opposed to non-smokers, in terms of smoking-related deficient inhibitory control. Hypothesis 2 stated the exact opposite, in terms of drug-tolerance. Results indicated no baseline differences. Nicotine enhanced inhibition more in non-smokers relative to smokers. Integrating the results, nicotine-abstinent smokers do not seem to resemble ADHD patients, and do not seem to smoke in order to self-medicate a pre-existing deficit pertaining to mechanisms of visuospatial attention and inhibition. Nicotine may affect inhibition more in non-smokers relative to smokers, consistent with a drug-tolerance account.

The effect of enhancing cholinergic neurotransmission by nicotine on EEG indices of inhibition in the human brain.

The role of the cholinergic system in inhibition remains to be elucidated. Nicotine is a potent tool to augment this system, but most studies investigated its effects solely on behavior. Reference to brain activity is important to specifically identify inhibition-related mechanisms. In the current study the objective was to elucidate the role of the cholinergic system in inhibition. 16 healthy non-smokers performed in a stop task while EEG was recorded. A pre- versus post-treatment, within subjects, placebo controlled, single-blind design was used. It was hypothesized that nicotine would decrease stop-signal reaction time (SSRT) and increase the amplitude of inhibition-related event related potentials, the stop N2 and stop P3. Behavioral measures show nicotine shortened SSRT, but only when pretreatment values were not taken into account. On EEG measures, an enhanced stop P3 under nicotine was found, but only in a subsample sensitive to nicotine based on diastolic blood pressure. The results are indicative of enhanced inhibitory activity possibly reflecting enhanced activation in the superior frontal gyrus.

The effect of the augmentation of cholinergic neurotransmission by nicotine on EEG indices of visuospatial attention.

The cholinergic system has been implicated in visuospatial attention but the exact role remains unclear. In visuospatial attention, bias refers to neuronal signals that modulate the sensitivity of sensory cortex, while disengagement refers to the decoupling of attention making reorienting possible. In the current study we investigated the effect of facilitating cholinergic neurotransmission by nicotine (Nicorette Freshmint 2mg, polacrilex chewing gum) on behavioral and electrophysiological indices of bias and disengagement. Sixteen non-smoking participants performed in a Visual Spatial Cueing (VSC) task while EEG was recorded. A randomized, single-blind, crossover design was implemented. Based on the scarce literature, it was expected that nicotine would specifically augment disengagement related processing, especially manifest as an increase of the modulation of the Late Positive Deflection (LPD) by validity of cueing. No effect was expected on bias related components (cue-locked: EDAN, LDAP; target-locked: P1 and N1 modulations). Results show weak indications for a reduction of the reaction time validity effect by nicotine, but only for half of the sample in which the validity effect on the pretest was largest. Nicotine reduced the result of bias as indexed by a reduced P1 modulation by validity, especially in subjects with strong peripheral responses to nicotine. Nicotine did not affect ERP manifestations of the directing of bias (EDAN, LDAP) or disengagement (LPD).

Electromyographic responses to emotional facial expressions in 6-7year olds: a feasibility study.

Preliminary studies have demonstrated that school-aged children (average age 9-10years) show mimicry responses to happy and angry facial expressions. The aim of the present study was to assess the feasibility of using facial electromyography (EMG) as a method to study facial mimicry responses in younger children aged 6-7years to emotional facial expressions of other children. Facial EMG activity to the presentation of dynamic emotional faces was recorded from the corrugator, zygomaticus, frontalis and depressor muscle in sixty-one healthy participants aged 6-7years. Results showed that the presentation of angry faces was associated with corrugator activation and zygomaticus relaxation, happy faces with an increase in zygomaticus and a decrease in corrugator activation, fearful faces with frontalis activation, and sad faces with a combination of corrugator and frontalis activation. This study demonstrates the feasibility of measuring facial EMG response to emotional facial expressions in 6-7year old children.

[Reversible metalation of a bis-disulfide analogue of the Cys*-X-Cys* hepcidin binding site: structural characterisation of the related copper complex]. / Métallation réversible d'un analogue bis-disulfure du site de liaison Cys*-X-Cys* de l'hepcidine: caractérisation structurale du complexe de cuivre associé.

Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the plasma and excreted in urine, is a key central regulator of body iron homeostasis. This hormone decreases export of cellular iron by binding to ferroportin, an iron exporter present at the basolateral surface of enterocytes and macrophages (the sites of dietary iron absorption and iron recycling, respectively), inducing its internalization and degradation. Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets. We noticed in the sequence of hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap iron and/or copper. We have tested this hypothesis using a pseudopeptidic synthetic bis-disulfide analogue and we have shown that direct metalation of such ligand leads to the formation of a copper(III) complex with the typical N(2)S(2) donor set. This compound crystallizes in the orthorhombic system, space group Imma. The Cu(III) configuration is square planar, built up from two carboximado-N and two thiolato-S donors. This complex is converted back to the bis-disulfide, with release of the copper salt, upon oxidation with iodine.

Arsenite medicinal use, metabolism, pharmacokinetics and monitoring in human hair.

Acute promyelocytic leukaemia (APL) is a distinctive subtype of acute myeloid leukaemias. Even through this human disease can be treated by the intravenous administration of all-trans retinoic acid (ATRA), 25% of patients typically relapse after the first treatment. In this context, the intravenous administration of APL patients with an aqueous solution of arsenic trioxide has also been demonstrated to be successful despite the established mammalian toxicity of this arsenic compound. Accordingly, the administration of a therapeutic dose of arsenic trioxide has resulted in an improved patient survival in both relapsing as well newly diagnosed APL patients. We present here a mini-review of the medicinal use of arsenite, its mammalian metabolism (with an emphasis on biomethylation pathways), its elimination and pharmacokinetics and the novel application of hair analysis as a biomonitoring material. This mini-review also introduces our own results on the analysis of hair of patients receiving arsenic trioxide therapy. In this work, instead of quantifying arsenic content in bulk hair, we performed longitudinal analysis in order to use hair as a marker of arsenic exposure correlated to a time scale. Taking into account the hair growth rate, the longitudinal analysis of hair is demonstrated to provide a chronological record of the treatment of patients with arsenic trioxide. The small quantity of material to be analysed required the use of Synchrotron radiation based X-ray fluorescence (SXRF) spectroscopy. The hair arsenic content was well correlated with the clinical background of patients and reflected the intake of arsenic trioxide. In particular, the onset of arsenic trioxide therapy and interruptions during therapy were reflected by total arsenic content, which suggested rapid elimination. Another type of experiment, micro-XRF cartography on thin hair slices, allowed us to obtain distribution maps of arsenic, which demonstrated that arsenic is located at the periphery of hair. Micro-XANES spectra recorded at the periphery of hair, suggest that inorganic arsenic is incorporated in hair in its trivalent oxidation state, in agreement with previous results.

[Stability of borderline personality disorder from childhood to adulthood: a literature review]. / Stabiliteit van de borderlinepersoonlijkheidsstoornis van de kinderjaren tot in de volwassenheid: Een literatuuronderzoek.

BACKGROUND: Borderline personality disorder (BPD) is a severe and frequent disorder. Little is known about its early stages, which can be in childhood or adolescence. AIM: To investigate to what extent BPD is stable from childhood through to adulthood. METHOD: The literature was systematically reviewed with the help of Medline, Psycinfo, embase and the Cochrane Library. RESULTS: Of children known to have BPD in the primary school age-group, 80% met the criteria for a personality disorder in adulthood and 16% met the criteria for BPD. In a population study of adults with bpd, 30% still met the criteria two years later. In groups of adolescents at risk the criteria were met by 15-30 % after two to three years. These groups also showed a low dimensional stability for BPD. The most stable symptoms were feelings of emptiness, anger, affect-instability and identity problems. Less stable symptoms were suicidality, self-harm, impulsiveness, unstable relationships, derealisation and paranoid thinking. CONCLUSIONS: Research into the stability of BPD that starts in children of primary school age has been too limited in a methodological sense for us to draw any firm conclusions. Research into BPD that starts in adolescence shows a low categorial and dimensional stability. Research into the onset of BPD in adults shows comparable low stability, but only after six years. In adolescents and adults impulsive and self-harm behaviour are probably the least stable symptoms and affective symptoms the most stable ones.

Atmospheric lead fallout over the last century recorded in Gulf of Lions sediments (Mediterranean Sea).

Six marine sediment cores from the Gulf of Lions continental slope (700-1700 m water depth) were analyzed for stable lead isotopes and (210)Pb geochronology in order to reconstruct lead atmospheric fallout pattern during the last century. The detrital lead contribution is 25 microg g(-1) and the mean sediment anthropogenic inventory is 110+/-7 microg cm(-2), a little bit higher than atmospheric deposition estimate. Anthropogenic lead accumulation in sediments peaked in early 1970s (1973+/-2) in agreement with lead emissions features. For the period 1986-1997, the sediment signal also reflect the decrease of atmospheric lead described by independent atmospheric fallout investigations. The anthropogenic Pb deposition in the late 1990s was similar to the 1950s deposition, attesting thus of the output of European environmental policies.

[BNP and dyspnea: proposition of a diagnostic strategy based on two cut-off]. / BNP et dyspnée: proposition d'une stratégie diagnostique basée sur deux seuils décisionnels de BNP.

The purpose of this study was to evaluate the cut-off value of brain natriuretic peptide (BNP) assayed with AxSYM BNP assay (Abbott). 86 patients have been included (mean age of 66 years). The clinical sensibility was 100% at 100 ng/L versus 80% at 250 ng/L. The clinical specificity was 66% at 100 ng/L versus 92% at 250 ng/L. The positive predictive value was 80% at 100 ng/L versus 92% at 250 ng/L. The negative predictive value was 100% at 100 ng/L versus 88% at 250 ng/L. The double cut-off strategy is more suitable to diagnose a dyspnea of cardiac origin than the usual strategy based on a single cut-off.value. With such a strategy, the two cut-off strategy improve the diagnosis of 9% in the total population.

[Proposal for a discriminant level of BNP in very elderly persons with heart failure]. / Proposition d'un seuil de BNP discriminant dans la population très âgée présentant une insuffisance cardiaque.

A diagnosis of heart failure (HF) in elderly patient can be difficult. The purpose of this study is to evaluate the cut-off of brain natriuretic peptide (BNP) Triage Assay (Biosite) in the diagnosis of HF in this population : 250 very older patients with age

[Utility of BNP measurement in the emergency room in patients with suspected unstable angina with a normal ECG]. / Utilité du dosage du BNP aux urgences chez les patients suspects d'angor instable avec ECG normal. A propos de 120 patients.

Unstable angina is a serious condition, difficult to diagnose in the emergency room. Clinical, electrocardiographic and biological signs (increased troponine) are not sensitive. The authors set out to assess whether measuring B natiuretic peptide in the emergency room was more sensitive for identifying symptomatic coronary lesions. One hundred and twenty patients admitted to the emergency room for chest pain compatible with the diagnosis of unstable angina and a normal ECG were included in this prospective study. All patients underwent coronary angiography during their hospital admission. The sensitivities of troponine at a threshold of 0.4 ng/ml and of brain natiuretic peptide (BNP) at a threshold of 10 pg/ml in this population were 66% and 92% respectively. The use of troponine and BNP together provided better results than troponine and BNP alone for the identification of patients with chest pain with significant coronary lesions.

[Value of type B natriuretic peptide in the emergency management of patients with suspected cardiac failure. Report of 125 cases]. / Apports du peptide natriurétique de type B dans la prise en charge aux urgences des patients suspects d'insuffisance cardiaque. A propos de 125 patients.

Shortness of breath is a common cause of consultation in the emergency unit. Therefore, it is essential to diagnose cases of cardiac failure. This may be difficult in some cases. The authors set out to assess the value of measuring brain natiuretic peptide in this context. Brain natiuretic peptide (BNP) was measured by an ultrafast method (Biosite/BMD) on arrival of 125 patients to the emergency unit. The results were then compared with the diagnoses made in the emergency unit and those of the hospital discharge summary. Nearly 18% of patients were wrongly classified in the emergency room; 1/3 were falsely diagnosed as cardiac failure and 2/3 were not recognised initially as having cardiac failure. In 90% of patients, in particular in the group wrongly considered as not having cardiac failure, BNP measurement could have helped correct the mistake. The optimal threshold value of BNP for diagnosis of cardiac failure in this study was 300 pg/mL, with positive and negative predictive values of 92.4 and 90.2%, respectively.

XAS applied to pharmaceuticals: drug administration and bioavailability.

We present selected XAS applications, focused towards practical hospital questions of drug administration and bioavailability, where the technique is driven up to its limits of sensitivity. i) XAS was used to study the interactions between the components of parenteral nutrition solutions, in particular zinc and aminoacids, possibly modifying their bioavailability. ii) We studied by EXAFS a series of binary and ternary copper-aminoacid complexes, in view of the development of an efficient oral drug against copper deficiencies in Menkes disease. iii) EXAFS and XANES analysis allowed us to characterise the solution form of a new arsenic containing drug against leukaemia. In parallel to the XAS measurements, we analysed trace elements levels along patients' hairs, using X-ray fluorescence excited by synchrotron radiation. The measurements along the hair allow for a monitoring of essential trace elements during therapy.