SAS CARE 1: Sleep architecture changes in a cohort of patients with Ischemic Stroke/TIA.

OBJECTIVE: Changes in sleep architecture following ischemic stroke have been poorly investigated. Our objective was to explore changes of sleep structure in patients with ischemic stroke or transient ischemic attack in order to verify a possible predictive value of sleep with respect to clinical outcome. METHODS: Patients recruited in the prospective SAS-CARE study received two polysomnographies (PSG) in the acute and chronic phases after stroke/TIA. Sleep parameters were compared between the two time-points and matched with a non-stroke population randomly selected from the HypnoLaus cohort. RESULTS: Of the 169 patients investigated with PSG in the acute phase, 104 were again studied 3 months after stroke symptom onset and compared with 162 controls. The acute phase of stroke/TIA was associated with sleep disruption, which significantly improved in the chronic phase, but remained worse than controls (total sleep time improve from 318.8 ± 90.8 to 348.4 ± 81.5 min, compared to 388.2 ± 71.3 in controls, sleep latency from 49.9 ± 58.4 to 27.9 min, compared to 20.2 ± 22 in controls, sleep efficiency from 58.2 ± 18.1% to 27.9 ± 36.4 min, compared to 83.4 ± 10.3% in controls, wakefulness after sleep onset percentage from 36.5 ± 17.3 to 29.3 ± 15.6, compared to 13.2 ± 9.2 in controls). The percentage of REM sleep was negatively associated with stroke severity, whereas stroke topography did not correlate with sleep parameters. CONCLUSIONS: This study confirmed a severe sleep disruption in the acute phase of stroke. Although a significant improvement of sleep quality was observed during the three months after stroke, sleep architecture did not normalize. In particular, sleep efficiency and REM sleep seem to be particularly affected by stroke in the acute phase, with a relative preservation of NREM sleep. We suggest that these sleep architecture changes represent a persistent marker of brain damage due to stroke. Further studies are needed to assess the relationship with stroke topographic and outcome.

A circuit perspective on narcolepsy.

The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or rapid eye movement (REM) sleep features including cataplexy, sleep paralysis, hallucinations, and sleep-onset REM sleep events (SOREMs). Although the loss of Hypocretin/Orexin (Hcrt/Ox) peptides or their receptors have been associated with the disease, here we propose a circuit perspective of the pathophysiological mechanisms of these narcolepsy symptoms that encompasses brain regions, neuronal circuits, cell types, and transmitters beyond the Hcrt/Ox system. We further discuss future experimental strategies to investigate brain-wide mechanisms of narcolepsy that will be essential for a better understanding and treatment of the disease.

Temporomandibular disorders and psychosocial status in osteogenesis imperfecta - a cross-sectional study.

BACKGROUND: Osteogenesis Imperfecta (OI) is characterized by a number of deviations in the orofacial region. The aims of the present study were to investigate the occurrence of temporomandibular disorders, to evaluate the psychosocial status, and to assess the dental occlusion in a population of adult OI patients. METHODS: Participants (n = 75) were classified with mild OI, type I (n = 56), or moderate-severe OI, type III and IV (n = 19). OI patients were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders (axis I and II). RESULTS: Temporomandibular disorders and functional limitations in the orofacial region were rare and did not differ between patients with mild and moderate-severe OI (P > 0.050). No significant differences between Graded Chronic Pain Scale grades 0, 1, and 2 were found in mild OI vs. moderate-severe OI (P > 0.160). Few patients (16%) had signs of depression, but close to half (48%) had signs of somatization. Patients with moderate-severe OI had a lower mean number of teeth compared to patients with mild OI (P <  0.050). In general, malocclusions were prevalent, and mandibular overjet and posterior cross-bite were found more often in moderate-severe OI compared with mild (P <  0.050). CONCLUSIONS: Patients with moderate-severe OI had more malocclusions than patients with mild OI. The psychosocial status of OI patients was remarkably healthy considering the severity of this disabling systemic disorder. The bodily pain complaints frequently reported in OI patients were not largely reflected in the orofacial area as painful temporomandibular disorders.

Monoamine oxidase A polymorphism moderates stability of attention problems and susceptibility to life stress during adolescence.

Attention problems affect a substantial number of children and adolescents and are predictive of academic underachievement and lower global adaptive functioning. Considerable variability has been observed with regard to the individual development of attention problems over time. In particular, the period of adolescence is characterized by substantial maturation of executive functioning including attentional processing, with the influence of genetic and environmental factors on individual trajectories not yet well understood. In the present investigation, we evaluated whether the monoamine oxidase A functional promoter polymorphism, MAOA-LPR, plays a role in determining continuity of parent-rated attention problems during adolescence. At the same time, a potential effect of severe life events (SLEs) was taken into account. A multi-group path analysis was used in a sample of 234 adolescents (149 males, 85 females) who took part in an epidemiological cohort study at the ages of 11 and 15 years. Attention problems during early adolescence were found to be a strong predictor of attention problems in middle adolescence. However, in carriers of the MAOA-LPR low-activity variant (MAOA-L), stability was found to be significantly higher than in carriers of the high-activity variant (MAOA-H). Additionally, only in MAOA-L carriers did SLEs during adolescence significantly impact on attention problems at the age of 15 years, implying a possible gene × environment interaction. To conclude, we found evidence that attention problems during adolescence in carriers of the MAOA-L allele are particularly stable and malleable to life stressors. The present results underline the usefulness of applying a more dynamic GxE perspective.

Evaluation of common structural brain changes in aging and Alzheimer disease with the use of an MRI-based brain atrophy and lesion index: a comparison between T1WI and T2WI at 1.5T and 3T.

BACKGROUND AND PURPOSE: The Brain Atrophy and Lesion Index combines several common, aging-related structural brain changes and has been validated for high-field MR imaging. In this study, we evaluated measurement properties of the Brain Atrophy and Lesion Index by use of T1WI and T2WI at 1.5T and 3T MR imaging to comprehensively assess the usefulness of the lower field-strength testing. MATERIALS AND METHODS: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative. Images of subjects (n = 127) who had T1WI and T2WI at both 3T and 1.5T on the same day were evaluated, applying the Brain Atrophy and Lesion Index rating. Criterion and construct validity and interrater agreement were tested for each field strength and image type. RESULTS: Regarding reliability, the intraclass correlation coefficients for the Brain Atrophy and Lesion Index score were consistently high (>0.81) across image type and field strength. Regarding construct validity, the Brain Atrophy and Lesion Index score differed among diagnostic groups, being lowest in people without cognitive impairment and highest in those with Alzheimer disease (F > 5.14; P < .007). Brain Atrophy and Lesion Index scores correlated with age (r > 0.37, P < .001) and cognitive performance (r > 0.38, P < .001) and were associated with positive amyloid-ß test (F > 3.96, P < .050). The T1WI and T2WI Brain Atrophy and Lesion Index scores were correlated (r > 0.93, P < .001), with the T2WI scores slightly greater than the T1WI scores (F > 4.25, P < .041). Regarding criterion validation of the 1.5T images, the 1.5T scores were highly correlated with the 3T Brain Atrophy and Lesion Index scores (r > 0.93, P < .001). CONCLUSIONS: The higher field and T2WI more sensitively detect subtle changes in the deep white matter and perivascular spaces in particular. Even so, 1.5T Brain Atrophy and Lesion Index scores are similar to those obtained by use of 3T images. The Brain Atrophy and Lesion Index may have use in quantifying the impact of dementia on brain structures.

Increasing association between a neuropeptide Y promoter polymorphism and body mass index during the course of development.

OBJECTIVE: To investigate the association of the neuropeptide Y (NPY) promoter polymorphism rs16147 with body mass index (BMI) during the course of development from infancy to adulthood. DESIGN: Longitudinal, prospective study of a German community sample. SUBJECTS: n = 306 young adults (139 males, 167 females). MEASUREMENTS: Participants' body weight and height were assessed at the ages of 3 months and 2, 4.5, 8, 11, 15 and 19 years. NPY rs16147 was genotyped. RESULTS: Controlling for a number of possible confounders, homozygote carriers of the rs16147 C allele exhibited significantly lower BMI scores when compared with individuals carrying the T allele. In addition, a significant genotype by age interaction emerged, indicating that the genotype effect increased during the course of development. CONCLUSIONS: This is the first longitudinal study to report an association between rs16147 and BMI during childhood and adolescence. The finding that this effect increased during the course of development may either be due to age-dependent alterations in gene expression or to maturation processes within the weight regulation circuits of the central nervous system.

Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1.

The Notch1-mediated signaling pathway has a central role in the maintenance of neural stem cells and contributes to growth and progression of glioblastomas, the most frequent malignant brain tumors in adults. Here, we demonstrate that the Notch1 receptor promotes survival of glioblastoma cells by regulation of the anti-apoptotic Mcl-1 protein. Notch1-dependent regulation of Mcl-1 occurs cell type dependent at a transcriptional or post-translational level and is mediated by the induction of epidermal growth factor receptor (EGFR). Inhibition of the Notch1 pathway overcomes apoptosis resistance and sensitizes glioblastoma cells to apoptosis induced by ionizing radiation, the death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or the Bcl-2/Bcl-XL inhibitor ABT-737. In conclusion, targeting Notch1 might represent a promising novel strategy in the treatment of glioblastomas.

Difficult double-lumen tube placement due to laryngeal web.

We present a case of difficult intubation in a patient with a laryngeal web. A 33-year-old male patient presented for open thoracotomy and had a previously undiagnosed laryngeal web, which complicated the placement of a double-lumen tube. A single-lumen tube was placed with the use of a bougie through the narrowed airway. With the subsequent use of an airway exchange catheter a double-lumen tube was positioned. Techniques for managing narrowing of the supraglottic airway are presented and the literature dealing with laryngeal webs is reviewed. In the setting of an unusual airway and thoracic surgery, ventilation via simpler techniques takes precedence over insertion of more complex tubes.

Early predictors of antisocial developmental pathways among boys and girls.

OBJECTIVE: We investigated in a high-risk sample the differential impact of biological and psychosocial risk factors on antisocial behaviour pathways. METHOD: One hundred and thirty-eight boys and 155 girls born at differing degrees of obstetric and psychosocial risk were examined from birth until adolescence. Childhood temperament was assessed by a highly-structured parent-interview and standardized behavioural observations, adolescent temperament was measured by self-report. Neurodevelopmental variables were assessed by age-specific developmental tests. Emotional and behaviour problems were measured at the ages of 8 and 15 by the Achenbach scales. RESULTS: In both genders, psychosocial adversity and early self-control temperament were strongly associated with early-onset persistent (EOP) antisocial behaviour. Psychosocial adversity and more severe externalizing problems differentiated the EOP from childhood-limited (CL) pathway. In girls, adolescent-onset (AO) antisocial behaviour was strongly associated with novelty seeking at 15 years. CONCLUSION: Our findings emphasize the need for early support and intervention in psychosocially disadvantaged families.

Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2.

Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in tumour cells but no Ang-2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang-2 in the tumour vasculature, whereas no Ang-1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within tumours.

Prospects for the classification of mental disorders of children and adolescents.

Suggestions for classification of mental disorders of children and adolescents in DSM-V and ICD-11 have been made, which differ strongly from the current descriptive approach of dimensional classification. These suggestions even comprise a dichotomized system for health care as well as for scientific purposes. Nevertheless it is obvious that we are far behind an "etiological" classification, so that trade-offs have necessarily to be made in DSM-V and ICD-11. Appropriate proposals concern the strict separation of disorders that are typical for children and adolescents as well as for adults. Furthermore a differentiation of diagnosis for infants, toddlers and preschool children is required in both classification systems. As far as it is relevant for treatment, combined diagnosis in DSM-V and subthreshold diagnosis as well as coding-possibilities for findings in molecular biology should be permitted. As personality disorders should only be diagnosed after the age of 16, it is recommended to dimensionally classify personality traits that are pathognomonic for specific symptom patterns and of prognostic relevance. DSM-V and ICD-11 should allow age-specific information on axis-IV. The article discusses the general question of how relational disorders respectively disturbances should be classified and include furthermore special recommendations concerning ICD and DSM categories.

Serotonin-induced platelet intracellular Ca2+ response in patients with anorexia nervosa.

INTRODUCTION: Serotonin (5-HT) is involved in the regulation of food intake. In anorexia nervosa there is a disturbance in 5-HT function. The stimulation of 5-HT(2)-receptors in platelets is a useful peripheral model to investigate the cascade of signal transduction and neuronal functioning. METHODS: 25 anorexic female patients between the ages of 11 and 18 years with a mean body mass index (BMI) of 13.9+/-1.3 kg/m(2) participated in this study. The 21 healthy female controls revealed a mean BMI of 20.5+/-2.7 kg/m(2). 5-HT stimulated intracellular Ca(2+) response of the platelets was obtained using the Fura-2 method at the time of admission, during therapy and when the target BMI was reached. RESULTS: We found a significant (p<0.01) decrease in 5-HT-induced Delta[Ca(2+)](i) at admission and a significant (p<0.05) increase of Delta[Ca(2+)](i) during treatment in patients with anorexia nervosa. Anorexic patients with and without comorbid depression had a comparable Ca(2+) release. However, low and high Ca(2+) responders showed a different course of Delta[Ca(2+)](i). The treatment with antidepressants led to a significant increase of Delta[Ca(2+)](i) in those patients with concomitant depression. DISCUSSION: Since the course of Delta[Ca(2+)](i) is not related to BMI or the presence of comorbid depression, we conclude that serotonergic transmission or signaling pathways could be disturbed in patients suffering from anorexia nervosa. One inference of this preliminary study is that administration of antidepressants may be more effective in patients with concomitant depression.

A novel mouse model for assessment of male sexual function.

A novel model to evaluate erectile, ejaculatory, and sexual behavior patterns in conscious mouse is presented. Corpus spongiosum of the penis (CSP) pressure was recorded by using telemetry and was correlated with erectile activity (penile elongations, cups, flips) during reflex induction and spontaneous erections in freely moving mice. CSP pressure was also recorded during mating tests (mounts, intromissions with erections, ejaculations), as well as non-contact tests with estrous female mice. Erectile events were quantified in four sexual contexts (spontaneous erections, spinal reflexes, in mating and non-contact tests). The data demonstrate that CSP pressure monitoring is a valid technique for assessment of sexual function in freely moving mice.

[Asperger syndrome - a too late diagnosed disorder?]. / Asperger-Syndrom - eine zu spät diagnostizierte Störung?

Asperger syndrome is a disorder within the autistic spectrum, which was first described by Hans Asperger in 1944. It belongs to the group of pervasive developmental disorders and is particularly characterized by qualitative impairments of social interaction and communication as well as distinct special interests and stereotyped patterns of behaviour. We present a patient, showing the typical behavioural symptoms of the Asperger syndrome, which were first diagnosed at the age of sixteen.

Association between ADHD and smoking in adolescence: shared genetic, environmental and psychopathological factors.

The present study aimed to examine the extent to which the co-occurrence of ADHD and smoking in adolescents could be attributed to common genetic, environmental and psychopathological factors. Data are from an ongoing prospective study of the outcome of early risk factors. At age 15 years, 305 adolescents completed self-report questionnaires measuring tobacco consumption and deviant peer affiliations. Lifetime psychiatric diagnoses were obtained using standardized interviews. DNA was genotyped for the dopamine D4 receptor (DRD4) gene exon III polymorphism. Adolescents with a lifetime diagnosis of ADHD displayed significantly higher smoking activity than non-ADHD controls. A major component of this association could be accounted for by deviant peer affiliations and the comorbidity with oppositional-defiant and conduct disorder, while a minor part was attributable to DRD4 in males but not in females. These findings suggest that the association of ADHD with smoking relies on risk factors shared by the two behaviors.

[The importance of choline and different serum parameters for the course of the anorexia nervosa]. / Die Bedeutung von Cholin und verschiedenen Serumparametern für den Verlauf der Anorexia nervosa.

Malnutrition in anorexia nervosa was simulated in an animal starvation study. Female rats aged 11 to 13 weeks received a hypocaloric standard diet or a hypocaloric choline reduced diet. Weight reduction lasted for 12 to 20 weeks and was between 30 % to 40 % of initial weight. Several animals were refed after weight reduction up to 6 to 12 weeks with a standard or a choline enriched diet ad libitum. Serum parameters and membrane fluidity of the CNS were measured after weight reduction or after refeeding. Weight reduction leads to a significant decrease of serum protein, triglycerides (Z = -3.53 resp. -3.42; p < 0.001) and an increase of membrane fluidity in the CNS (Z = -2.83; p < 0.001). Long-term diet with marked weight reduction and following refeeding causes a catabole metabolic situation with significant increase of urea/creatinine-ratio. Choline enriched refeeding after diet results in normalization of serum parameters and membrane fluidity of the CNS. Choline enrichment leads to a significant increase of serum protein (Z = -2.03; p < 0.01). Besides we found a negative correlation between serum protein and urea/creatinine-ratio (r (S) = -0.47; p < 0.001; n = 64). This is possibly caused by a reduced protein catabolism or an increased protein anabolism. Furthermore membrane fluidity in the CNS correlates with serum protein (r (S) = 0.65; p < 0.001; n = 41) and with serum creatinine levels (r (S) = 0.58; p < 0.001; n = 42). We conclude that these serum parameters are potential predictors for cell function in the starved brain and consequently for the course of anorexia nervosa. We furthermore hypothesize that choline enriched nutrition after starvation improves the stabilization of cerebral membranes and the metabolic situation in anorexia nervosa.

[Methylphenidate double-blind trial: indication and performing]. / Der Methylphenidat-Doppelblindversuch--Indikation und Durchführung.

Hyperkinetic disorders or attention-deficit/hyperactivity disorders (ADHD) are among the psychiatric diagnoses most often encountered in children and adolescents. Symptoms include inattention, hyperactivity and impulsivity. Within the multi-modal treatment system, the therapy with psychostimulants (e. g. methylphenidate) proved to be an effective in patients with ADHD. A double-blind trial is indicated in cases of unclear efficacy of methylphenidate at initial application or if psychostimulants have regularly been applied for more than one year with an leave-out trial delivering unequivocal results. Further it is helpful in verifying potential undesirable side effects and improving patients' compliance.

Is the serotonin transporter polymorphism (5-HTTLPR) associated with harm avoidance and internalising problems in childhood and adolescence?

The S allele of the 5-HTTLPR has been associated with anxiety-related behavioural traits and harm avoidance. The 5-HTTLPR polymorphism is suggested to modulate the serotonergic response to stress, meaning that individuals carrying the SS genotype who have significant stress histories may tend to develop depressive symptoms. In the Mannheim Study of Risk Children, which followed a cohort of n = 384 from birth to adolescence, the association of 5-HTTLPR with harm avoidance and internalising problems was examined, including gender and early life stress as possible moderators. Child and adolescent characteristics were assessed using the Junior Temperament and Character Inventory, the Child Behaviour Checklist and the Youth Self Report. Early life stress was determined by a risk index measuring the presence of 11 adversity factors. Results did not reveal an association with 5-HTTLPR genotype. There were no moderating effects of early life stress or gender. An explanation for the negative findings is that the S allele may be a necessary but not sufficient component cause in a composite risk factor.

Interaction between the dopamine D4 receptor and the serotonin transporter promoter polymorphisms in alcohol and tobacco use among 15-year-olds.

Early onset of alcohol and tobacco use during adolescence increases the risk for establishing a substance use disorder in adulthood. Both alcohol and nicotine stimulate the dopamine (DA) and the serotonin (5-HT) systems. The DA system has been implicated in the mediation of the rewarding effects of self-administered drugs of abuse. A possible role of an interaction between these neurotransmitter systems in substance use behavior has been suggested but is as yet unknown. The present study was designed to examine the influence of the DA D4 receptor (DRD4) and the serotonin transporter (5-HTT) genotype and their interaction on adolescent alcohol and tobacco experimentation. Participants were from a longitudinal study of a birth cohort consisting initially of 384 children from a high-risk community sample. At the age of 15 years, adolescents completed a self-report questionnaire measuring tobacco and alcohol consumption. DNA was taken from 305 participants (146 boys, 159 girls) and genotyped for the DRD4 exon III and the 5-HTTLPR polymorphisms. The DRD4 7-repeat allele was associated with greater smoking and drinking involvement in boys. In girls, a significant DRD4 x 5-HTT interaction was detected. Girls without the DRD4 7-repeat allele and who were homozygous for the long allele of 5-HTTLPR displayed the highest smoking and drinking activity. The genetic and potential molecular background underlying adolescent vulnerability to substance abuse is discussed.