Search

Sleep and cognition in children and adolescents Abstract. In this review, one of the most important functions of sleep was described: Its role in promoting cognitive processes in children and adolescents. Particularly, studies of older children and adolescents revealed that sleep interacts in a complex manner with cognitive performance. Moreover, it was shown that sleep supports long-term memory even in young children. This is true for many different long-term memory systems such as memory of factual information (declarative memory), language acquisition, and for reward-related learning, but less so for learning motor skills. Clinical implications arise from observing the consequences of sleep deficits in children and adolescents due to early school hours or due to clinical conditions like attention deficits hyperactive disorder (ADHD), sleep apnea syndrome or other sleep disturbances. Current research has only partially shown that the treatment of sleep problems also benefits cognitive and memory performance. Filling this gap remains an opportunity for further research.Zusammenfassung. In diesem Überblicksartikel beschäftigen wir uns mit einer der wichtigsten Aufgaben des Schlafs, nämlich der Förderung kognitiver Prozesse bei Kindern und Jugendlichen. Bislang wurde überwiegend bei älteren Kindern und Jugendlichen beschrieben, dass der Schlaf die kognitive Leistungsfähigkeit auf komplexe Weise beeinflusst. Schon bei sehr jungen Kindern wurde nachgewiesen, dass der Schlaf eine fördernde Funktion in vielen Bereichen des Langzeitgedächtnisses aufweist. Hierzu gehören das Faktenwissen (deklaratives Gedächtnis) sowie das Erlernen von Sprache und das Lernen aus Belohnung. Hingegen fördert Schlaf bei Kindern die Konsolidierung motorischer Fertigkeiten nur unter bestimmten Voraussetzungen. Klinische Implikationen ergeben sich aus den Beobachtungen der Folgen von Schlafmangel bei Kindern und Jugendlichen aufgrund des frühen Schulbeginns, aber auch aus Untersuchungen von verschiedenen Störungsbildern wie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS), dem Schlafapnoesyndrom und anderen Schlafstörungen. Nur teilweise wurde bisher gezeigt, dass eine Behandlung der Störungen des Schlafs auch zu verbesserten Kognitions- oder Gedächtnisleistungen führt. Dies bleibt eine Herausforderung zukünftiger Forschungsanstrengungen.

AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens. METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radio- and chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18F-fluorodeoxyglucose (FDG) and proliferation with 18F-fluorothymidine. RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines (HROC126, HROC284Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/ non-MSI-H (sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APCwt, TP53wt, KRASwt, BRAFwt, PTENwt; HROC239 T0 M1: APCmut, P53wt, KRASmut, BRAFwt, PTENmut and HROC284Met: APCwt, P53mut, KRASmut, BRAFwt, PTENmut. All cell lines could be characterized as epithelial (EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.

Sleep-related breathing disorders seriously impair well-being and increase the risk for relevant somatic and psychiatric disorders. Moreover, risk factors for sleep-related breathing disorders are highly prevalent in psychiatric patients. The aim of this study was for the first time in Germany to study the prevalence of obstructive sleep apnea syndrome (OSAS) as the most common form of sleep-related breathing disorder in patients with psychiatric disorders.In 10 psychiatric hospitals in Germany and 1 hospital in Switzerland, a total of 249 inpatients underwent an 8‑channel sleep polygraphy to investigate the prevalence of sleep apnea in this group of patients.With a conspicuous screening result of 23.7% of the subjects, a high prevalence of sleep-related breathing disorders was found to occur among this group of patients. Male gender, higher age and high body mass index (BMI) were identified as positive risk factors for the detection of OSAS.The high prevalence indicates that sleep apnea is a common sleep disorder among psychiatric patients. Although OSAS can lead to substantial disorders of the mental state and when untreated is accompanied by serious somatic health problems, screening procedures are not part of the routine work-up in psychiatric hospitals; therefore, sleep apnea is presumably underdiagnosed in psychiatric patients. In view of the results of this and previous studies, this topic complex should be the subject of further research studies.

AIM To establish cell line and patient-derived xenograft (PDX) models for neuroendocrine carcinomas (NEC) which is highly desirable for gaining insight into tumor development as well as preclinical research including biomarker testing and drug response prediction. METHODS Cell line establishment was conducted from direct in vitro culturing of colonic NEC tissue (HROC57). A PDX could also successfully be established from vitally frozen tumor samples. Morphological features, invasive and migratory behavior of the HROC57 cells as well as expression of neuroendocrine markers were vastly analyzed. Phenotypic analysis was done by microscopy and multicolor flow cytometry. The extensive molecular-pathological profiling included mutation analysis, assessment of chromosomal and microsatellite instability; and in addition, fingerprinting (i.e., STR analysis) was performed from the cell line in direct comparison to primary patient-derived tissues and the PDX model established. Drug responsiveness was examined for a panel of chemotherapeutics in clinical use for the treatment of solid cancers. RESULTS The established cell line HROC57 showed distinct morphological and molecular features of a poorly differentiated large-cell NEC with KI-67 > 50%. Molecular-pathological analysis revealed a CpG island promoter methylation positive cell line with microsatellite instability being absent. The following mutation profile was observed: KRAS (wt), BRAF (mut). A high sensitivity to etoposide, cisplatin and 5-FU could be demonstrated while it was more resistant towards rapamycin. CONCLUSION We successfully established and characterized a novel patient-derived NEC cell line in parallel to a PDX model as a useful tool for further analysis of the biological characteristics and for development of novel diagnostic and therapeutic options for NEC.

The authors aimed at analyzing the costs of inpatient care of schizophrenia in Kiel (Germany). The study was also to present treatment regimens used at the German Academic Center. Moreover, the study is a continuation and complement of the previous study conducted in Polish and Ukrainian Academic Center. Therefore, it helps increase the awareness and knowledge of residents concerning the cost of inpatient care of schizophrenia. The analysis was based on 105 hospital records of patients treated between January 2012 and June 2013. According to inclusion criteria, 50 adult patients (27 women and 23 men) were included in the study. The study was approved by the Ethics Committee of the Medicine Faculty of CAU in Kiel. The cost of schizophrenia treatment of 50 patients in Kiel was EUR 604,280.90 (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\bar{x}$$\end{document}x¯ = EUR 12,085.62). The duration of hospital stay was on average \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\bar{x}$$\end{document}x¯ = 51.02 days. The patients were treated with neuroleptics of all generations. The most popular atypical neuroleptic was amisulpride and the most popular typical neuroleptic was haloperidol. Patients from Kiel were provided a comprehensive non-pharmacological treatment. Treatment regiments and evaluations of costs of schizophrenia vary between countries. The costs of inpatient care of schizophrenia are high in Kiel. Treatment of schizophrenia seems to be comprehensive in Kiel and wide range of treatment opportunities contribute to a more effective treatment confirmed by less frequent relapses of schizophrenia than in Lviv (Ukraine), for example. Comprehensive treatment should be available everywhere, because it is a right of every patient.

Gedächtnis und Schlaf sind basale Funktionen unseres Lebens. Durch unser Gedächtnis werden die einzelnen Momente unseres Erlebens zusammengefügt und wir können uns als Individuum erleben. Die Gedächtnisbildung wird besonders durch den Schlaf gefördert. Es gibt mittlerweile eine Reihe von Hinweisen darauf, dass bei bestimmten Störungen des Schlafes die schlafbezogene Gedächtnisbildung ebenfalls beeinträchtigt ist.

The present study aimed to explore dynamic and interactive aspects of cosleep in heterosexual couples. The sample consisted of eight young healthy adults who belonged to four heterosexual couples with a good relationship quality and a history of cosleeping. All individuals underwent simultaneous polysomnography in a sleep laboratory for four nights in which they slept individually and with their partner. Also, a sleep protocol of subjective sleep measures was completed. Statistical analyses included cross recurrence quantification analysis to assess synchronization during sleep. Cosleeping was associated with better subjective sleep quality, increased total sleep time, sleep efficiency, total slow wave sleep, and REM sleep. Sleep stages were more synchronized during cosleep independent of awakenings. Cardiorespiratory measures remained unchanged. The results indicate that young healthy couples in good relationships benefit from cosleeping on a subjective and objective level. Combining simultaneous polysomnography and cross recurrence quantification analysis is a promising method to study dynamic and interactive aspects of cosleep possibly leading to deeper understanding of the role of sleep for sociality, the nature of REM sleep, and the partner as a social zeitgeber. Moreover, clinical implications may arise from these findings.

The transcription factors NF-kappaB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines promote signaling cascades that lead to the co-regulation of p53 and NF-kappaB. Consequently, nuclear p53/NF-kappaB signaling complexes activate NF-kappaB-dependent survival genes. The 18 histone deacetylases (HDACs) are epigenetic modulators that fall into four classes (I-IV). Inhibitors of histone deacetylases (HDACi) become increasingly appreciated as anti-cancer agents. Based on their effects on p53 and NF-kappaB, we addressed whether clinically relevant HDACi affect the NF-kappaB/p53 crosstalk. The chemotherapeutics hydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-kappaB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells. Using specific HDACi, we find that the class I subgroup of HDACs, but not the class IIb deacetylase HDAC6, are required for the hydroxyurea-induced crosstalk between p53 and NF-kappaB. HDACi decrease the basal and stress-induced expression of p53 and block NF-kappaB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53.

Autophagy is a lysosome-dependent, intracellular pathway for the recycling of cellular components. It plays a pivotal role in both cancer development and the response to chemotherapy. Here we describe how autophagy can be monitored in living cells by flow cytometry using the cationic amphiphilic tracer dye Cyto-ID

DNA fiber spreading assay is an invaluable technique to visualize and follow the spatial and temporal progress of individual DNA replication forks. It provides information on the DNA replication progress and its regulation under normal conditions as well as on replication stress induced by environmental genotoxic agents or cancer drugs. The method relies on the detection of incorporated thymidine analogues during DNA synthesis in the S phase of the cell cycle by indirect immunofluorescence. Here, we describe the procedure established in our laboratories for sequential pulse labeling of human cells with 5-chloro-2'-deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU), cell lysis, and DNA fiber spreading on slides and sequential immunodetection of the incorporated thymidine analogues by primary antibodies recognizing specifically CldU or IdU alone. We describe also the laser scanning imaging, classification, and measurement of the detected DNA fiber tracks. The obtained quantitative data can be evaluated statistically to reveal the immediate or long-term effects of DNA-damaging agents, DNA repair inhibitors, and epigenetic modulators like HDAC inhibitors on DNA replication in normal and tumor cells.

Autophagy is a lysosome-dependent, intracellular pathway for the recycling of cellular components. It plays a pivotal role in both cancer development and the response to chemotherapy. Here we describe how autophagy can be monitored in living cells by flow cytometry using the cationic amphiphilic tracer dye Cyto-ID® Green. The detection of autophagy induction in the human leukemia cell line K562 after the treatment with the HDAC class I inhibitor MS-275 serves as an example for this approach.

DNA fiber spreading assay is an invaluable technique to visualize and follow the spatial and temporal progress of individual DNA replication forks. It provides information on the DNA replication progress and its regulation under normal conditions as well as on replication stress induced by environmental genotoxic agents or cancer drugs. The method relies on the detection of incorporated thymidine analogues during DNA synthesis in the S phase of the cell cycle by indirect immunofluorescence. Here, we describe the procedure established in our laboratories for sequential pulse labeling of human cells with 5-chloro-2'-deoxyuridine (CldU) and 5-iodo-2'-deoxyuridine (IdU), cell lysis, and DNA fiber spreading on slides and sequential immunodetection of the incorporated thymidine analogues by primary antibodies recognizing specifically CldU or IdU alone. We describe also the laser scanning imaging, classification, and measurement of the detected DNA fiber tracks. The obtained quantitative data can be evaluated statistically to reveal the immediate or long-term effects of DNA-damaging agents, DNA repair inhibitors, and epigenetic modulators like HDAC inhibitors on DNA replication in normal and tumor cells.

Background and objectives Patients with schizophrenia reveal impaired decision-making strategies causing social, financial and health care problems. The extent to which deficits in decision-making reflect intentional risky choices in schizophrenia is still under debate. Based on previous studies we expected patients with schizophrenia to reveal a riskier performance on the GDT and to make more disadvantageous decisions on the IGT. Methods In the present study, we investigated 38 patients with schizophrenia and 38 matched healthy control subjects with two competing paradigms regarding feedback: (1) The Game of Dice Task (GDT), in which the probabilities of winning or losing are stable and explicitly disclosed to the subject, to assess decision-making under risk and (2) the Iowa Gambling Task (IGT), which requires subjects to infer the probabilities of winning or losing from feedback, to investigate decision-making under ambiguity. Results Patients with schizophrenia revealed an overall riskier performance on the GDT; although they adjusted their strategy over the course of the GDT, they still made significantly more disadvantageous choices than controls. More positive symptoms in patients with schizophrenia indicated by higher PANSS positive scores were associated with riskier choices and less use of negative feedback. Compared to healthy controls, they were not impaired in net score but chose more disadvantageous cards than controls on the first block of the IGT. Limitations Effects of medication at the time of testing cannot be ruled out. Conclusions Our findings suggest that patients with schizophrenia make riskier decisions and are less able to regulate their decision-making to implement advantageous strategies, even when the probabilities of winning or losing are explicitly disclosed. The dissociation between performance on the GDT and IGT suggests a pronounced impairment of executive functions related to the dorsolateral prefrontal cortex.

Background The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep–wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy. Methods In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography. Results Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions. Conclusion In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.

Objective Sleep supports the consolidation of declarative memory. Patients with attention-deficit/hyperactivity disorder (ADHD) are not only characterized by sleep problems but also by declarative memory deficits. Given that the consolidation of declarative memory during sleep is supported by slow oscillations, which are predominantly generated by the prefrontal cortex, and that ADHD patients display low prefrontal brain activity, we assumed that ADHD patients show reduced sleep-associated consolidation of declarative memory. Methods The impact of sleep on the consolidation of declarative memory was examined with a picture recognition task. Twelve ADHD patients (10–16 years) and 12 healthy controls participated in two experimental conditions: in the sleep condition, learning was performed in the evening and picture recognition was tested after nocturnal sleep; in the wake condition, learning was conducted in the morning while retrieval took place after a day of wakefulness. Results Analyses of recognition accuracy revealed reduced sleep-associated enhancement of recognition accuracy in ADHD. While sleep-associated enhancement of recognition accuracy was correlated with slow oscillation power during non-REM sleep in healthy controls, no such correlations were observed in ADHD. Conclusions These data indicate a deficit in sleep-associated consolidation of declarative memory in ADHD. Moreover, our results suggest reduced functionality of slow oscillations in sleep-associated consolidation of declarative memory in ADHD.

It has been hypothesized that non-rapid eye movement (NREM) sleep facilitates declarative memory consolidation, and rapid eye movement (REM) sleep is particularly important in promoting procedural learning. The aim of this study was to examine the effects of pharmacological REM sleep suppression on performance in different neuropsychological tasks. For our baseline, we chose 41 moderately depressed patients (age range 19-44 years), who were not taking antidepressants. In the morning after polysomnography, we tested memory recall and cognitive flexibility by assessment of verbal and figural fluency, a shift of attention task and the Trail Making Test B. After recording baseline values, patients were assigned randomly to one of three treatment groups: medication with citalopram; medication with reboxetine; or exclusive treatment with psychotherapy. Retesting took place 1 week after onset of treatment. The main results were: (1) an association of slow-wave sleep with verbal memory performance at baseline; (2) a suppression of REM sleep in patients taking citalopram and reboxetine; (3) no differences regarding neuropsychological performance within the treatment groups; and (4) no association of REM sleep diminution with decreases in memory performance or cognitive flexibility in patients treated with citalopram or reboxetine. In line with other studies, our results suggest that there are no negative effects of a decrease in REM sleep on memory performance in patients taking antidepressants.

Although the consolidation of several memory systems is enhanced by sleep in adults, recent studies suggest that sleep supports declarative memory but not procedural memory in children. In the current study, the influence of sleep on emotional declarative memory (recognition task) and procedural memory (mirror tracing task) in 20 healthy children (10-13 years of age) was examined. After sleep, children showed an improvement in declarative memory. Separate analysis with respect to the emotional stimulus content revealed that sleep enhances the recognition of emotional stimuli (p>.001) rather than neutral stimuli (p=.084). In the procedural task, however, no sleep-enhanced memory improvement was observed. The results indicate that sleep in children, comparable to adults, enhances predominantly emotional declarative memory; however, in contrast to adults, it has no effect on the consolidation of procedural memory.

Background: The cyclic adenosine monophosphate response element-binding proteins (CREB) and their interaction with brain-derived neurotrophic factor (BDNF) are essential elements in signal transduction pathways important for cellular resilience and neuroplasticity. They play a decisive role in the concept of altered neuroplasticity in major depression. We have previously demonstrated that the increase in phosphorylated CREB (pCREB) in T lymphocytes is significantly associated with clinical improvement in patients treated with antidepressants. In the present study, we focused on patients treated only with psychotherapy to exclude direct pharmacological actions. In addition to pCREB, we also measured the BDNF plasma levels. Methods: pCREB in T lymphocytes was determined by Western blot; the BDNF plasma levels with solid-phase ELISA. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Thirty patients meeting DSM-IV criteria for major depressive episodes (MDE) were recruited into this 6-week study. They received interpersonal psychotherapy (IPT) twice weekly. Results: After 6 weeks of IPT, 17 patients responded (reduction of ≥50% of baseline HAMD); after 1 week of treatment pCREB increased significantly compared to the nonresponder group. Measurement of the BDNF plasma levels revealed no differences between the responder and nonresponder groups. Furthermore, the correlations between BDNF plasma levels and pCREB were not significant. Conclusions: The early increase in pCREB is related to treatment response and does not depend on pharmacological interventions or BDNF plasma levels. For the first time, cellular biological markers could be associated with response to psychotherapy.

Introduction Memory deficits and sleep disturbances are common clinical features of schizophrenia. Sleep is supposed to promote memory consolidation and the antipsychotic olanzapine is suggested to improve both sleep and memory functions. Therefore we performed a study to analyse the acute effects of olanzapine on distinct sleep parameters and sleep-related memory consolidation in parallel. Methods We studied 26 patients with schizophrenia on stable antipsychotic medication with amisulpride (age range 19-44 years). Immediately before polysomnography and the morning after we performed neuropsychological tasks. Before the third night in the sleep laboratory, patients received either olanzapine or a placebo. Results We found a significant positive association for slow wave sleep and declarative memory performance in schizophrenia at baseline. Additionally, Stage 2 sleep spindle density was positively related to overnight memory consolidation. Olanzapine caused a significant increase in the amount of slow wave sleep in accordance with recent studies, but led also to a significant decrease in sleep spindle density, which had not been described before. Memory performance the next morning was not different between the two groups. Discussion Since not only slow wave sleep but also sleep spindles are supposed to promote sleep-related memory consolidation, we suggest that a putative positive effect on memory performance by slow wave sleep augmentation is neutralised by the decrease in sleep spindles due to olanzapine.

Background: Behavioral inhibition, which is a later-developing executive function (EF) and anatomically located in prefrontal areas, is impaired in attention-deficit and hyperactivity disorder (ADHD). While optimal EFs have been shown to depend on efficient sleep in healthy subjects, the impact of sleep problems, frequently reported in ADHD, remains elusive. Findings of macroscopic sleep changes in ADHD are inconsistent, but there is emerging evidence for distinct microscopic changes with a focus on prefrontal cortical regions and non-rapid eye movement (non-REM) slow-wave sleep. Recently, slow oscillations (SO) during non-REM sleep were found to be less functional and, as such, may be involved in sleep-dependent memory impairments in ADHD. Objective:By augmenting slow-wave power through bilateral, slow oscillating transcranial direct current stimulation (so-tDCS, frequency = 0.75 Hz) during non-REM sleep, we aimed to improve daytime behavioral inhibition in children with ADHD. Methods: Fourteen boys (10–14 years) diagnosed with ADHD were included. In a randomized, double-blind, cross-over design, patients received so-tDCS either in the first or in the second experimental sleep night. Inhibition control was assessed with a visuomotor go/no-go task. Intrinsic alertness was assessed with a simple stimulus response task. To control for visuomotor performance, motor memory was assessed with a finger sequence tapping task. Results: SO-power was enhanced during early non-REM sleep, accompanied by slowed reaction times and decreased standard deviations of reaction times, in the go/no-go task after so-tDCS. In contrast, intrinsic alertness, and motor memory performance were not improved by so-tDCS. Conclusion: Since behavioral inhibition but not intrinsic alertness or motor memory was improved by so-tDCS, our results suggest that lateral prefrontal slow oscillations during sleep might play a specific role for executive functioning in ADHD.

Schizophrenia is a severe and chronic disorder requiring long-lasting and comprehensive treatment. Because of this disorder patients are socially isolated. Consequently, schizophrenia has a significant economic burden both in a group of direct and indirect costs. The aim was to analyse experts’ opinions in the field of psychiatry concerning work possibilities among people with schizophrenia and to present the importance of employment for more effective treatment. A worldwide study was conducted between June 2011 and June 2013 using a questionnaire consisting of six open-closed questions and a short metrics. The questionnaire was delivered to experts and spread all over the world by post and via the internet. Over 3000 questionnaires were sent and the addressed specialists were requested to return them. From received 403 questionnaires 320 were included into the study, based on adopted inclusion and exclusion criteria. Although patients are afraid of looking for a job, respondents indicated that they crave for employment. The number of people that are able to work during remission of schizophrenia is considerably higher (50.35 %) than the number of actually employed (15.85 %). Non-pharmacological therapies were indicated as important to improve patients′ chances of finding a job during remission of schizophrenia. The number of people that can work during remission of schizophrenia is considerably higher than the number of affected people employed. Patients crave for a job and supported employment should be treated as priority by health-care decision makers.

The neurotransmitter orexin has been shown to modulate wakefulness and sleep and other functions regarding cognition and the metabolic system. Because of the link between orexin-A deficiency and the disorder narcolepsy, effects of orexin on sleep and wakefulness are of particular interest for clinical purposes. Indeed, the transfer of results of animal studies to study protocols with humans is problematic. The utilized methods used in animals are not realizable in patients for ethical reasons, such as intracerebroventricular injection, possible side effects, and less effectiveness of intravenous and oral orexin. One way to avoid these problems is the intranasal administration of drugs. We present rare results of the relatively new procedure for administering orexin.

Alkylating agents are present in food and tobacco smoke, but are also used in cancer chemotherapy, inducing the DNA lesion O (6)-methylguanine. This critical adduct is repaired by O (6)-methylguanine-DNA methyltransferase (MGMT), resulting in MGMT inactivation and degradation. In the present study, we analyzed the effects of the natural disulfide compound lipoic acid (LA) on MGMT in vitro and in colorectal cancer cells. We show that LA, but not its reduced form dihydrolipoic acid, potently inhibits the activity of recombinant MGMT by interfering with its catalytic Cys-145 residue, which was partially reversible by N-acetyl cysteine. Incubation of HCT116 colorectal cancer cells with LA altered their glutathione pool and caused a decline in MGMT activity. This was mirrored by LA-induced depletion of MGMT protein, which was not attributable to changes in MGMT messenger RNA levels. Loss of MGMT protein coincided with LA-induced autophagy, a process resulting in lysosomal degradation of proteins, including presumably MGMT. LA-stimulated autophagy in a p53-independent manner as revealed by the response of isogenic HCT116 cell lines. Knockdown of the crucial autophagy component beclin-1 and chemical inhibitors blocked LA-induced autophagy, but did not abrogate LA-triggered MGMT degradation. Concomitant with MGMT depletion, LA pretreatment resulted in enhanced O (6)-methylguanine levels in DNA. It also increased the cytotoxicity of the alkylating anticancer drug temozolomide in temozolomide-resistant colorectal cancer cells. Taken together, our study showed that the natural compound LA inhibits MGMT and induces autophagy. Furthermore, LA enhanced the cytotoxic effects of temozolomide, which makes it a candidate for a supplement in cancer therapy.