The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H.

The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial-to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

[Rationing in inpatient psychiatric care]. / Rationierung in der stationären psychiatrischen Versorgung.

OBJECTIVE: This study examined whether and in which services in psychiatric institutions implicit rationing takes place from the perspective of doctors and nurses. METHODS: From October 2013 to the middle of 2014 we conducted a written and standardized survey among physicians/psychologists (n = 256) and nurses (n = 796) from eight psychiatric hospitals in Germany. RESULTS: Out of 11 clinical activities 4 judged as necessary, namely communication and interaction with patients and relatives, coordination of treatment with other professionals and adequate documentation of the treatment, were not carried out sufficiently or implicitly rationed by 42-59% of the surveyed physicians/psychologists. Multivariate analysis identified a higher case load, poor relationships with superiors and an overall heavy workload as significant predictors of implicit rationing. DISCUSSION: The services which are particularly necessary for an effective treatment of mentally ill people, i.e. strong patient orientation and close cooperation with other professionals are jeopardized by the implicit rationing.

[Recommendations for psychotherapy in psychiatric inpatient treatment : Results of the PAKT Study Part I]. / Psychotherapieempfehlungen in der stationären psychiatrisch-psychotherapeutischen Behandlung : Ergebnisse der PAKT-Studie Teil I.

BACKROUND: In the S3 treatment guidelines psychotherapy is recommended in all psychological disorders. Therefore, outpatient or inpatient psychotherapy should be recommended by therapists in most cases. On the other hand, it is well known that waiting periods for psychotherapeutic treatment are considerable, which raises the question how the recommendation for psychotherapy is presented in psychiatric hospitals in Germany. OBJECTIVES: The article deals with the question of how frequent the recommendation of psychotherapeutic treatment is made after psychiatric inpatient stay or day care, and if there are differences between hospitals and patient groups. METHOD: In four psychiatric hospitals in southern Germany the frequency of recommendation for psychotherapy in psychiatric patients was registered and compared to the number of all patients treated in the equivalent time. For this purpose, we analyzed data of the basic documentation in the four participating hospitals. RESULTS: Overall, 9.6 % of the patients received a recommendation of psychotherapeutic treatment. In the psychiatric university hospital a subsequent psychotherapeutic treatment was recommended somewhat more often. Differences between hospitals were present but marginal. Over all participating hospitals, psychotherapy was recommended markedly less frequently in patients with an F2 diagnosis in comparison with patients with F3 or F4 diagnoses. CONCLUSION: Psychotherapeutic treatment after psychiatric inpatient stay is recommended cautiously. Probably therapists anticipate the fact that the growing demand for psychotherapeutic treatment in general reduces the chances for persons after psychiatric inpatient treatment.

[Implementation of the recommendations for psychotherapy after psychiatric inpatient treatment : Results of the PAKT study Part II]. / Realisierung von Psychotherapieempfehlungen nach psychiatrischem Aufenthalt : Ergebnisse der PAKT-Studie Teil II.

BACKGROUND: Waiting periods for inpatient or outpatient psychotherapeutic treatment are generally considerable. For patients treated in a psychiatric day-clinic or hospital, implementation of a recommended subsequent psychotherapeutic treatment might be difficult. OBJECTIVES: In part II of the psychotherapy after hospital or day clinic (PAKT) study, we examined how the recommendation for psychotherapy can be implemented after psychiatric treatment. MATERIALS AND METHODS: Three months after discharge from one of four psychiatric hospitals in southern Germany, we interviewed 306 patients who received a recommendation for psychotherapeutic treatment after their hospital stays if the recommendation was implemented successfully. RESULTS: Only about 12 % of the patients in the follow-up group were unable to implement the general recommendation for psychotherapy after psychiatric stay despite motivation for psychotherapeutic treatment. In the case of recommendation for outpatient psychotherapy, 20 % were unsuccessful. Predictors for successful implementation were education and employment, whereas variables like age, gender, diagnosis, or severity of disorder did not play a significant role. CONCLUSIONS: The relatively small percentage of unimplemented psychotherapeutic treatment is surprising at a first glance. However, the proportion recommended for psychotherapy after psychiatric stay was less than 10 %, as shown in the first part of the study (see PAKT Study Part I, doi:s00115-016-0107-z).

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia.

BACKGROUND: Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. METHOD: The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. RESULTS: Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. CONCLUSIONS: The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Who is Subjected to Coercive Measures as a Psychiatric Inpatient? A Multi-Level Analysis.

BACKGROUND: For a reduction in the use of coercive interventions it will be necessary to identify patients at risk. The aim of this study was to explore the impact of basic patient characteristics at admission, history within 24 hours before admission, and living conditions on the risk of experiencing coercive measures, controlling for ward characteristics in a multi-level approach. METHODS: Patient characteristics of 3389 patients (1920 women) who had received inpatient treatment in 2007, data relating to coercive measures, and ward characteristics were extracted from the clinical basic documentation. RESULTS: Patients with aggressive behaviour in the 24 hours prior to admission had a three times higher risk of coercive measures compared to non-aggressive patients. Severity of illness increased the risk of coercion markedly. With each level of severity, the risk of coercion was doubled. Voluntariness of stay appeared to be the best protective factor against coercive measures. If a patient stayed voluntarily, this reduced the risk of coercion by more than two thirds. No impact was found for living conditions. CONCLUSIONS: To identify patients at risk, it is most important to intensively monitor patients with aggressive behaviour prior to admission and patients with a greater severity of psychopathological symptoms.

[Repeated measurement of memory with valenced test items: verbal memory, working memory and autobiographic memory]. / Messwiederholung von Gedächtnistests unter Berücksichtigung der Valenz des Testmaterials: verbales Gedächtnis, Arbeitsgedächtnis und autobiografisches Gedächtnis.

A large number of questions in clinical and/or experimental neuropsychology require the multiple repetition of memory tests at relatively short intervals. Studies on the impact of the associated exercise and interference effects on the validity of the test results are rare. Moreover, hardly any neuropsychological instruments exist to date to record the memory performance with several parallel versions in which the emotional valence of the test material is also taken into consideration. The aim of the present study was to test whether a working memory test (WST, a digit-span task with neutral or negative distraction stimuli) devised by our workgroup can be used with repeated measurements. This question was also examined in parallel versions of a wordlist learning paradigm and an autobiographical memory test (AMT). Both tests contained stimuli with neutral, positive and negative valence. Twenty-four participants completed the memory testing including the working memory test and three versions of a wordlist and the AMT at intervals of a week apiece (measuring points 1. - 3.). The results reveal consistent performances across the three measuring points in the working and autobiographical memory test. The valence of the stimulus material did not influence the memory performance. In the delayed recall of the wordlist an improvement in memory performance over time was seen. The tests on working memory presented and the parallel versions for the declarative and autobiographical memory constitute informal economic instruments within the scope of the measurement repeatability designs. While the WST and AMT are appropriate for study designs with repeated measurements at relatively short intervals, longer intervals might seem more favourable for the use of wordlist learning paradigms.

Controlling the orbital sequence in individual Cu-phthalocyanine molecules.

We report on the controlled change of the energetic ordering of molecular orbitals. Negatively charged copper(II)phthalocyanine on NaCl/Cu(100) undergoes a Jahn-Teller distortion that lifts the degeneracy of two frontier orbitals. The energetic order of the levels can be controlled by Au and Ag atoms in the vicinity of the molecule. As only one of the states is occupied, the control of the energetic order is accompanied by bistable changes of the charge distribution inside the molecule, rendering it a bistable switch.

[Cognitive deficits and psychiatric disorders in patients with new-onset epilepsy]. / Kognitive Defizite und psychiatrische Störungen in Frühstadien epileptischer Erkrankungen.

From a theoretical point of view it may be hypothezised that cognitive deficits are not uncommon in patients with new-onset epilepsy since causative brain lesions, genetic influences and interictal epileptic activity are likely to exist even before the first unprovoked seizure. We reviewed the literature concerning cognitive deficits in genetically determined epilepsy-syndromes and studies on cognitive and psychiatric deficits in patients with new-onset epilepsy. In several animal models hints of memory deficits or learning disorders even before the manifestation of epileptic seizures were found. Some learning disorders showed characteristics of the human attention-deficit-hyperactivity-disorder. In familial frontal epilepsies specific associations between cognitive deficits as well as psychiatric syndromes and certain mutations were described. Cognitive deficits in adult patients with new-onset epilepsy were described several times with regard to delayed recall in verbal memory, selective attention and psychomotor performance. Depression and suicide attempts were increased before the first seizure. In childhood cognitive deficits were regarded as causative factors for behavioral problems, which sometimes were even found before the first recognized seizure. Verbal memory deficits at the onset of epilepsy seemed to be a risk factor for the development of a therapy refractory course. But on the basis of the published data it is impossible to state whether cognitive deficits after a first unprovoked seizure in adulthood indicate an increased risk of recurrent seizures apart from the results of MRI and EEG studies.

[On the value of neuropsychological short tests in epileptology]. / Zur Wertigkeit neuropsychologischer Kurztests in der Epileptologie.

Cognitive deficits are common in patients with epilepsy refractive to therapy and have considerable influence on the quality of life in this group of patients. Therefore, neuropsychological investigations should play an important role in the comprehensive evaluation of patients with chronic epilepsy. The aim of this study was to examine whether a reliable screening for cognitive deficits in these patients may be reduced to the assessment of two bedside tests. In a prospective study we analyzed the results of 40 patients with epilepsy refractive to therapy subjected to a 45-min neuropsychological screening battery and compared them with the results of a short battery consisting of two bedside tests. Using the screening battery as the gold standard, the short battery had a sensitivity of 50% and a specificity of 100%. Changing the criteria for pathological results in the short battery, sensitivity could be raised to 81.25% but specificity fell to 50%. Therefore, bedside tests instead of longer neuropsychological testing cannot be recommended as a screening method for cognitive deficits in patients with chronic epilepsy.

[Influence of age at onset, age and duration of illness on cognitive abilities in patients with refractory epilepsy]. / Der Einfluss von Erkrankungsalter, Lebensalter und Krankheitsdauer auf die kognitiven Leistungen bei Patienten mit therapierefraktärer Epilepsie.

This retrospective study was performed as part of the controversial discussion whether increasing cognitive deficits in patients with refractory epilepsy are mainly an effect of normal aging or caused by epilepsy related noxious events during the course of an intractable epilepsy. Neuropsychological data and information about the course of the disease from 146 patients with refractory epilepsy were available. There were significant correlations between the age at onset and premorbid intelligence, duration of disease and fluid intelligence and age and difference between premorbid intelligence and fluid intelligence as a measure of cognitive deterioration. Discussing these results we conclude that beneath a clear effect of normal aging on cognitive deterioration there is probably a small effect of the refractory course of the epilepsy, which might be mediated by the number of seizures. Additionally we would like to encourage early cognitive screening and rehabilitation programmes for patients with epilepsy to minimize the effect of the age of onset on the level of education or premorbid intelligence.

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs.

BACKGROUND: Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. OBJECTIVE: This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. METHODS: We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. RESULTS: There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. CONCLUSIONS: Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

Modification of slow cortical potentials in patients with refractory epilepsy: a controlled outcome study.

PURPOSE: To compare self-regulation of low-frequency EEG components (slow cortical potentials, SCPs) with other methods of seizure control for patients with drug-refractory partial epilepsy and to separate the real anticonvulsive effect from placebo effects. METHODS: Results of a treatment program of SCP self-regulation (experimental group) are compared with two groups of patients, one of which learned self-control of respiratory parameters (end-tidal CO2 and respiration rate: RES group); the other received medication with new anticonvulsive drugs (AEDs) in combination with psychosocial counseling (MED group). Clinical, cognitive, behavioral, and personality measures were assessed before and after treatment. In addition, to control for placebo responses, patients repeatedly estimated their beliefs in the efficiency of the respective treatment, their satisfaction and expectations, and the quality of the relationship with their therapists. RESULTS: SCP and MED groups showed a significant decrease of seizure frequency, but the RES group did not. Clear positive changes in the sociopsychological adjustment were obtained in all three groups, with the maximal improvement being attained in the RES group. CONCLUSIONS: All kinds of therapy result in considerable improvement of patients' emotional state, which may in part be due to potential placebo effects: however, this improvement is not related to the quality of the therapeutic effect proper (i.e., seizure reduction). Traditional double-blind control group designs are inappropriate for behavioral interventions or treatments with psychoactive pharmacologic drugs. Rather, specific tests can be developed to control the placebo effect and to separate it from the genuine therapeutic effects.

Biofeedback treatment in patients with refractory epilepsy: changes in depression and control orientation.

Depression is a common and serious interictal problem in patients with epilepsy. The genesis of depressive disorders is multifactorial. One aetiological aspect focuses on psychosocial factors. It was hypothesized that uncontrollable, unpredictable chronic aversive events (i.e. epileptic seizures) result in cognitive deficits of external control orientation. If this is true, biofeedback training could represent a possible treatment strategy to lower depression, because biofeedback is known to mediate success experiences and control. Measures of depression and locus of control were administered to 20 patients with refractory partial epilepsy before and after biofeedback treatment. The biofeedback consisted of slow cortical potentials or breathing parameters in 10 patients each. A clear relationship occurred between depression and locus of control in the subjects. After biofeedback training control orientation moved towards a more internal locus of control. Also, depression scores were significantly reduced six months after training. Results show that in patients with refractory epilepsy depression is highly correlated with locus of control, in a way that external control orientation relates to high depression scores. Biofeedback is able to improve internal control orientation through personal success mediation.

Beyond habituation: long-term repetition effects on visual event-related potentials in epileptic patients.

Sixteen patients with partial epilepsy learned to produce positive or negative slow cortical potential shifts in a biofeedback condition during 20 consecutive training sessions. Visual ERPs to the presentation of the feedback and the discriminative stimulus were recorded at vertex. Regardless of the subjects' task (positivity versus negativity), amplitudes of the P2 (mean peak latency about 225 ms) and P3a (322 ms) components decreased across sessions, resulting in appearance and subsequent enhancement of a negative wave N2 (298 ms) between P2 and P3a. As N2 grew the P2 latency decreased and the P3a latency increased. Additionally, the P3b (472 ms) decreased with repetition, however, it did so slower than P2 and P3a. A comparison between the present data, on the one hand, and those obtained in the ERP habituation paradigm within one session, on the other hand, indicates that some repetition effects cannot be explained by habituation.

Self-regulation of slow cortical potentials in epilepsy: a retrial with analysis of influencing factors.

Twenty sessions of biofeedback training were carried out with 12 drug-resistant patients with focal epilepsy who learned to produce either negative or positive shifts of their slow cortical potentials (SCPs) at vertex. Feedback trials were interspersed with transfer trials in which only a discriminative stimulus (signalizing whether positivity or negativity was required) was presented, without feedback signal. Patients were able to differentiate significantly between the conditions of cortical positivity and cortical negativity, with larger differentiation scores being obtained in feedback trials than in transfer trials. The amplitude of positivity generated in the positivity condition increased linearly across sessions both in feedback and in transfer trials. The largest negativity was produced in the 5th session; after this, more transient negativities were generated, whose amplitude decreased towards the end of trial. The mean severity of seizures, estimated as the frequency of seizures weighted by their subjective 'strength', decreased significantly after training as compared to the pre-training phase. The data suggest that (1) patients could learn to achieve a state of cortical disfacilitation and (2) with progressed learning, they became less motivated for (or afraid of) producing considerable negative shifts, since extensive negativity may reflect cortical over-excitation and therefore be associated with early signs of seizures. The inability of producing cortical negativity is however not necessarily a bad predictor.

The body's response to processing emotional trauma: linking verbal text with autonomic activity.

When individuals talk or think about upsetting experiences, different coping and defensive processes are invoked from one minute to the next. Further, some coping strategies are thought to be more effortful and to be associated with greater biological activity than others. The present research sought to identify how the expression of emotions and the use of different psychological defenses were reflected in momentary changes in autonomic nervous system activity while subjects wrote about emotional topics. A new methodology is introduced that links the production of natural written language with autonomic activity on a word-by-word or phrase-by-phrase basis. Using this technique with a sample of 24 subjects who wrote about traumatic experiences, it was found that certain text dimensions are highly related to skin conductance level (SCL) but not heart rate. In general, subjects' SCLs increased when expressing negative emotions and when using denial and the passive voice. SCLs were more likely to drop when subjects used positive emotion words and self-references and at the conclusion of sentences or thought units. Implications for this methodology for understanding psychological defense and physical health are discussed.

A cross-sectional study of ethylene glycol monomethyl ether process employees.

Human exposures to ethylene glycol monomethyl ether have been associated with hematological and neurological abnormalities. Recent animal toxicology studies have also reported testicular atrophy. To determine whether employees potentially exposed to ethylene glycol monomethyl ether during manufacturing and packaging had a higher prevalence of anemia, leukopenia, or sterility than an in-plant comparison group, a cross-sectional study was conducted at the Michigan Division of Dow Chemical U.S.A. Blood samples on 65 of 97 potentially exposed and control white males, and semen samples from a subset of 15 were analyzed. With the possible exception of smaller testicular size, no gross abnormalities or clinically meaningful differences in hematological or fertility indices were noted. Results of regression modeling suggested that white blood cells and hemoglobin might be decreased at higher exposure levels.

Nasopharyngeal and adjacent neoplasms: a clinico-pathologic and immunologic study.

Thirteen cases of nasopharyngeal carcinoma (NPC) and 16 cases of non-NPC tumors in the nasopharynx or in adjacent locations were investigated clinically, immunologically, and pathologically. All tumors were classified according to the TNM classification, and the stage and course of the disease was correlated with the histological tumor type, the T- and B-cell distribution in tumor tissue and in the peripheral blood, as well as with antibody titers against Epstein-Barr virus (EBV). The results showed a positive correlation of decreased T- and B-cells in tumor tissue and of decreased T-cells in the peripheral blood with the extend of the tumor in both NPC and non-NPC cases, with some exceptions of lymphocyte rich neoplasms (lymphoepithelial carcinoma and malignant lymphoma). Antibodies against EBV (early antigen and capsid antigen) became progressively elevated with increasing tumor stage in NPC-cases but not in non-NPC cases. The latter, however, was observed only in two histological types of NPC's: anaplastic carcinoma and lymphoepithelial carcinoma; titers in the remaining tumor types stayed insignificant.

Percent distribution of T- and B-cells in tonsils of children, juveniles and adults.

The percent distribution of T- and B-lymphocytes in tonsilar tissue of 122 patients from 2--68 years and both sexes was investigated. T-cells were determined by the E-rosetting technique and B-cells by immunofluorescence. We found 50.3% B-cells and 30.6% T-cells in tonsilar tissue. There was a significant decrease of IgM-receptor carrying cells with increasing age and with a converse behavior of the sum of IgA-, IgD-, IgE-receptor B-cells. In tonsils with acute inflammation and with hyperplasia IgM cells were also increased significantly when compared to cell counts in chronic tonsillitis. The results are discussed and compared to data from the literature.