Estimation of a preliminary therapeutic reference range for children and adolescents with tic disorders treated with tiapride.

PURPOSE: Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated. METHODS: Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures. RESULTS: In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97-19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs. CONCLUSIONS: This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).

Texture differentiation using audio signal analysis with robotic interventional instruments.

Robotic minimally invasive surgery (RMIS) has played an important role in the last decades. In traditional surgery, surgeons rely on palpation using their hands. However, during RMIS, surgeons use the visual-haptics technique to compensate the missing sense of touch. Various sensors have been widely used to retrieve this natural sense, but there are still issues like integration, costs, sterilization and the small sensing area that prevent such approaches from being applied. A new method based on acoustic emission has been recently proposed for acquiring audio information from tool-tissue interaction during minimally invasive procedures that provide user guidance feedback. In this work the concept was adapted for acquiring audio information from a RMIS grasper and a first proof of concept is presented. Interactions of the grasper with various artificial and biological texture samples were recorded and analyzed using advanced signal processing and a clear correlation between audio spectral components and the tested texture were identified.

Experimental analysis of the mechanical behavior of the viscoelastic porcine pancreas and preliminary case study on the human pancreas.

The aim of this article is to study the mechanical properties of the pancreas. Up to now, the mechanical properties of the pancreas are not sufficiently characterized. The possibility of intraoperative mechanical testing of pathological pancreata will allow the classification of pancreatic diseases in the future. The application of mechanical parameters instead of the intraoperative frozen section analysis shortens waiting times in the operating room. This study proves the general applicability of shear rheology for the determination of the mechanical properties of pancreas and the assessment of graft quality for transplantation. Porcine and human pancreas samples were examined ex vivo and a nonlinear viscoelastic behavior was observed. Pancreas was found to be more viscous than liver but both abdominal organs showed a similar flow behavior. The shear deformation dependence of healthy human pancreas was similar to porcine pancreas. An increase in the post-mortem time led to an increase in the complex modulus for a post-mortem time up to 8.5 days. Histological investigations showed that an increased amount of collagen coincides with the stiffening of the pancreatic tissue.

How preservation time changes the linear viscoelastic properties of porcine liver.

The preservation time of a liver graft is one of the crucial factors for the success of a liver transplantation. Grafts are kept in a preservation solution to delay cell destruction and cellular edema and to maximize organ function after transplantation. However, longer preservation times are not always avoidable. In this paper we focus on the mechanical changes of porcine liver with increasing preservation time, in order to establish an indicator for the quality of a liver graft dependent on preservation time. A time interval of 26 h was covered and the rheological properties of liver tissue studied using a stress-controlled rheometer. For samples of 1 h preservation time 0.8% strain was found as the limit of linear viscoelasticity. With increasing preservation time a decrease in the complex shear modulus as an indicator for stiffness was observed for the frequency range from 0.1 to 10 Hz. A simple fractional derivative representation of the Kelvin Voigt model was applied to gain further information about the changes of the mechanical properties of liver with increasing preservation time. Within the small shear rate interval of 0.0001-0.01 s⁻¹ the liver showed Newtonian-like flow behavior.

[Successful closure of a postoperative esophagobronchial fistula following esophageal resection using fibrin glue]. / Erfolgreicher Fibrinkleber-basierter Verschluss einer postoperativen ösophagobronchialen Fistel nach Ösophagusresektion.

UNLABELLED: HISTORY AND INTERVENTION: A 52-year-old female patient underwent open abdominothoracic cardia and esophageal resection with gastric transposition because of histologically diagnosed Barrett metaplasia with "high-grade" intraepithelial neoplasia (HGIEN) and parts of an invasive adenocarcinoma. The anastomotic insufficiency on the 10th postoperative day including an esophagobronchial fistula prompted to a subsequent surgical re-intervention with suture of the fistula, lavage and additional drainage, an endoscopic stenting of the fistula from esophageal site, as well as repeated (n = 22) bronchoscopic applications of fibrin glue (1-3 ml each) into the lumen of the fistula after each bronchoscopic lavage of the fistula until the complete closure was achieved. The changeful clinical course of 77 days on the surgical ICU was characterized by secondary complications such as pneumonia, mediastinitis and respiratory insufficiency with long-term artificial respiration and creation of a percutaneous dilatation tracheotomy. CONCLUSION: The application of fibrin glue can be considered a promising, minimally invasive therapeutic option in the management of postoperative fistula after esophageal resection, which requires expertise in decision-making and the finding-specific approach, in particular, if indicated inital steps of the sequential complication management such as surgical re-intervention and conventional endoscopic measures (stenting, Endo-VAC[-sponge]) do not provide great therapeutic potential any more due to the prolonged postoperative time course and the unfavorable local findings. In the presented case, modes of an assisted artificial respiration with low pressure and short phases of apnoe after fibrin glue application were the crucial predictions for an initial and favorable adhesion of this glue and finally for a successful sealing resulting in a sufficient closure of the fistula.

Therapeutic drug monitoring of children and adolescents treated with fluoxetine.

INTRODUCTION: Information about therapeutic serum levels of fluoxetine (FLX) and its major metabolite norfluoxetine (NORFLX) in children and adolescents is scarce. METHODS: Therapeutic drug monitoring (TDM) of FLX was routinely performed in 71 subjects treated for a major depressive disorder (MDD) (10-60 mg/d FLX, median: 20 mg/d). Correlations between serum concentration and dosage, age, gender, smoking habits and adverse events were analysed. RESULTS: Serum concentrations of the active moiety (FLX + NORFLX) ranged from 21 to 613 ng/mL (mean concentration of 213 ± 118 ng/mL, median: 185 ng/mL). High inter-individual variability in serum concentrations of the active moiety of FLX at each dosage level was observed and no relationship between serum concentration and clinical outcome was found. Apart from smoking, none of the factors tested had a significant eff ect on the serum concentration. DISCUSSION: It was shown that serum concentrations of the active moiety of FLX in children and adolescents seem to be similar to those in adults, with a high level of inter-individual variation. The proportion of patients who showed benefits from treatment with a dose of 20 mg/d FLX was high.

Therapeutic drug monitoring in child and adolescent psychiatry.

Psychopharmacotherapy in children and adolescents is characterized by an increased susceptibility for adverse events and an increased risk of ineffective treatment due to specific age-dependent and developmental characteristics in comparison to adults. Dosing in paediatric psychiatric patients requires careful handling, since the dose recommendations for adults can not simply be extrapolated to minors because of pharmacokinetic and pharmacodynamic differences. In addition, psychopharmacotherapy in children and adolescents is hampered by lack of high quality evidence on efficacy and safety in many indications and subsequently a high degree of off-label use. Therapeutic Drug Monitoring (TDM) is an established and useful tool in psychiatry to individualize and optimize the outcomes (efficacy/safety balance) of psychopharmacological drug treatment in the individual patient by dose adjustments based upon measured serum concentrations. In children and adolescents the administration of psychotropic drugs is a general indication for performing TDM. However, TDM studies specific in these age groups are necessary to identify age and indication specific therapeutic ranges of serum concentrations. Systematic collection of data on drug exposure, serum concentrations and clinical characteristics as well as outcomes can generate such practice-based evidence. A German-Swiss-Austrian competence network for TDM in child and adolescent psychiatry using a multi-centre internet-based data infrastructure was founded to document and collect demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents (further information: www.tdm-kjp.com).

Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia.

INTRODUCTION: Marked inter-individual variation has been observed with respect to the risk of weight gain and related metabolic disturbances during antipsychotic treatment, which in part could be explained by heritability. Such adverse effects have been proposed to occur through drug-induced mechanisms involving both the central nervous system and different peripheral tissues. METHODS: We genotyped tagSNPs in several genes ( ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAG1, PRKAG2, PRKAG3, FTO and FABP3) that regulate lipid and energy homeostasis for their possible association to antipsychotic-induced weight gain. RESULTS: In a sample of 160 patients of German origin with schizophrenia who had been monitored with respect to body weight, we found marked association between antipsychotic-related changes in BMI and 6 markers in the adiponectin gene ( ADIPOQ). DISCUSSION: These findings support previous observations (in patients' serum) that adiponectin is involved in antipsychotic-mediated metabolic adverse effects.

[Palliative chemotherapy for colorectal cancer--current state, significance, trends]. / Palliative Chemotherapie beim kolorektalen Karzinom--Stand, Wertigkeit, Tendenzen.

BACKGROUND: There are a number of effective substances available for palliative treatment of colorectal cancer, contributing to a considerable extension of the median survival time either purely medically or by increasing the chance of secondary resectability through improved effectiveness of the administered drugs. PATIENTS / MATERIAL: Defining treatment depending on predominant patient characteristics remains crucial for any therapeutic success. This requires interdisciplinary co-ordination within tumour boards. METHODS: In aggressive tumours a therapeutic approach inducing high response rates is favoured, usually including a triple or quadruple combination incl. antibodies. In cases of slow tumour progress and limited patient profile, a sequence of chemotherapy is chosen. Implementing and integrating locally ablative modes of therapy into the treatment strategy can increase the effectiveness additionally. In a best case scenario additional systemic side effects can be avoided resulting in a not insignificant benefit in quality of life. RESULTS: Further genotyping beyond the K-RAS state is necessary to make predictive and prognostic statements concerning the drugs applied and to avoid ineffectiveness. CONCLUSION: Considerable progress has been achieved in the medical therapy for metastasised colorectal cancer. The targeted application of already available as well as recently developed substances requires further evaluation by appropriate studies.

Serum concentrations, therapeutic response and side effects in children and adolescents with impulsive-aggressive symptoms during risperidone therapy.

INTRODUCTION: The aim of this prospective naturalistic study was to examine for the first time the relationship between dosage, serum concentration and clinical outcome in children and adolescents with impulsive-aggressive symptoms during risperidone therapy. METHODS: Steady state trough serum concentrations of risperidone and 9-hydroxyrisperidone (the active moiety) were measured in 103 subjects. The therapeutic effect was assessed by the clinical global impression improvement subscale and side effects by the Udvalg for Kliniske Undersogelser-side effect rating scale. RESULTS: We found a linear relationship between the risperidone dose and the serum concentration of the active moiety (Spearman rho=0.53) and no correlation between the serum concentration and either the therapeutic effect or side effects. There was no effect of gender and co-medication. DISCUSSION: This study has the typical limitations of naturalistic studies, therefore our results should be interpreted with caution. Based on the serum concentrations at the therapeutically effective dose range (0.25-1.5 mg/day) we obtained first information on a possibly appropriate therapeutic serum range for the risperidone treatment of children and adolescents with impulsive-aggressive symptoms. Further studies with greater sample sizes are needed to validate our results and to examine the influence of genetic polymorphisms on the serum concentration of risperidone.

Trait anxiety in children and adolescents with anorexia nervosa.

In this study of trait anxiety in children and adolescents with anorexia nervosa, a consecutive series of 23 newly admitted children and adolescents with anorexia nervosa was studied by use of the State-Trait-Anxiety-Inventory, the Eating Disorders Inventory (EDI), the Social Phobia and Anxiety Inventory for Children (SPAI-C), and a structured psychiatric interview (DIPS: Diagnostisches Interview bei psychischen Störungen). In addition, clinical diagnoses were taken from the files. Trait anxiety was significantly increased at the time of admission and social phobia was present in a large proportion of the patients. Specific eating disorder psychopathology as measured by the EDI was significantly associated with trait anxiety. There were no clinical diagnoses (according to the International Classification of Diseases - Tenth Revision) of anxiety disorders. Features of anxiety are very common in young patients with anorexia nervosa and closely linked to specific psychopathology. Anxiety disorders need careful evaluation in these patients.

Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1 and INSIG2) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (P=0.0003-0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.

Therapeutic drug monitoring of quetiapine in adolescents with psychotic disorders.

INTRODUCTION: There are developmental and age-dependent differences in the pharmacokinetics and the pharmacodynamics of drugs in children and adolescents. Therefore, there is a need to carry out standardised studies to find out therapeutic ranges of plasma/serum concentrations in psychopharmacotherapy of children and adolescents. The aim of this prospective study was to examine the relationship between quetiapine serum concentration, treatment response, and side effects in a clinical setting to elucidate the age-specific therapeutic range of quetiapine in adolescents. METHODS: Over a period of two years, therapeutic drug monitoring (TDM) was routinely performed in 21 adolescents (mean age was 15.9+/-1.5 years, 57% male) with psychotic disorders according to the guidelines of the AGNP TDM expert group. The psychopathology was assessed by using the Clinical Global Impression Scale (CGI) and the Brief Psychiatric Rating Scale (BPRS). Side effects were assessed by using the Dose Record and Treatment Emergent Symptom Scale (DOTES). Trough quetiapine concentrations were determined under steady state conditions after multiple-dose regimes (median 600 mg/day; range 100-800 mg/day). RESULTS: There was a marked variability of the serum concentrations, ranging from 19-877 ng/ml. 40.8% of the determined values were below and 24.5% above the therapeutic range (70-170 ng/ml) recommended for adults. None of the patients had severe side effects. We found a weak correlation between dose and serum concentration of quetiapine and no relationship between serum concentration and treatment response. DISCUSSION: There are several limitations of this study, and our results should therefore be interpreted with caution. Notwithstanding, differences in the ontogenesis of pharmacokinetics and pharmacodynamics may be the reason for the difference in the relationship between blood concentrations and therapeutic response to psychopharmaca in children, adolescents and adults. Further studies using larger samples, baseline assessment of psychopathology, definition of the treatment interval and investigation of clinically relevant interactions with various co-medications are warranted to improve the limitations of this pilot study.

Weight gain associated with clozapine, olanzapine and risperidone in children and adolescents.

The study was aimed at the evaluation of weight gain associated with atypical antipsychotics and its clinical risk factors in children and adolescents. Weight and body mass index (BMI) of initially hospitalised patients treated with clozapine (n = 15), olanzapine (n = 15), and risperidone (n = 15) were prospectively monitored on a weekly basis for the first 6 weeks. Different clinical risk factors were tested for their association with weight gain in the three groups. All three groups experienced significant weight gain between baseline and endpoint (p < 0.0001). For all weight measures, planned comparisons were all significant between olanzapine vs. clozapine and risperidone, respectively. Average weight gain was significantly higher for the olanzapine group (mean = 4.6 kg, SD = 1.9) than for the risperidone (mean = 2.8 kg, SD = 1.3) and clozapine (mean = 2.5 kg, SD = 2.9) groups. Olanzapine and risperidone, but not clozapine, caused a disproportionately higher weight gain in children and adolescents in comparison to adults.

[Dysmorphophobia]. / Mein Gesicht ist eine Fratze!

In the ICD-10 classification, the body dysmorphophobic (dysmorphic) disorder is subsumed under the code for somatoform or hypochondriacal disorders (F45.2). To the fore is an excessive preoccupation with an imagined, but not objectifiable, bodily defect, usually affecting a part of the body that is either exposed or considered to be of importance for the patient's attractiveness. In many cases, the patient insistently demands surgical correction. During the further course of the condition, depression, social phobia, obsessive-compulsive and self-destructive behavior may develop. The condition usually begins early in the patient's life, and the lifetime prevalence is estimated to be 5%. Since an involvement of the serotonergic system is assumed, selective serotonin reuptake inhibitors are considered to be the medication of first choice. Surgical interventions do not lead to remission but simply to a transference of symptoms. Referral to a psychiatric specialist with the aim of clarifying the diagnosis is indicated.

Microarray analysis reveals distinct gene expression patterns in the mouse cortex following chronic neuroleptic and stimulant treatment: implications for body weight changes.

Atypical neuroleptics are associated with clinical significant weight gain, whereas stimulants are used as anorexiant drugs. The aim of this study was to examine gene expression changes in the mouse frontal cortex following chronic oral treatment with antipsychotics and a stimulant by microarray assessments. Twenty 10-12-week-old male C57BL6 mice received daily for 31 days either the typical neuroleptic haloperidol (1 mg/kg), the atypical neuroleptic clozapine (10 mg/kg) or the stimulant phenylpropanolamine (3 mg/kg). We identified a set of genes that was differently expressed between the neuroleptic-treated groups and the stimulant-treated group. Importantly, we found in the majority of gene alterations down-regulation in genes involved in ATP biosynthesis and lipid metabolism following the stimulant treatment, suggesting these genes as candidates that may regulate body weight. We also identified remarkable expression patterns of genes that encode signalling molecules (e.g. insulin, mitochondrial uncoupling protein 1) that are implicated in the control of food intake and are differently expressed in the neuroleptic groups.

Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder.

The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.