Prevalence of suicidal ideation in German psychotherapy outpatients: A large multicenter assessment.

BACKGROUND: Suicidal ideation is a major concern in clinical practice. Yet, little is known about prevalence rates of suicidal ideation in patients undergoing outpatient psychotherapeutic treatment. Therefore, the aim of the current study is to assess the prevalence of suicidal ideation in a large sample of psychotherapy outpatients in Germany. The data analyzed in this study is taken from the KODAP-project on the coordination of data collection and analysis at German university-based research and training outpatient clinics for psychotherapy. METHODS: A total of N = 10,357 adult outpatients (64.4 % female; age: M(SD) = 35.94 (13.54), range: 18-92 years of age) starting cognitive-behavioral therapy at one of 27 outpatient clinics in Germany were included in the current study. Prevalence of suicidal ideation was assessed with the Suicide Item (Item 9) of the Beck-Depression Inventory II. RESULTS: Suicidal ideation was reported by 36.7 % (n = 3795) of the participants. Borderline Personality Disorder, Posttraumatic Stress Disorder, and recurrent Major Depression were the diagnoses most strongly associated with the presence and severity of suicidal ideation. LIMITATION: Suicide ideation was assessed only with the respective item of the Beck Depression Inventory II. CONCLUSION: Suicidal ideation is very common among adult patients who start psychotherapy in Germany. A well-founded knowledge of risk assessment in suicidal patients and suicide-specific treatment options is therefore highly relevant.

Genome-wide single nucleotide polymorphism analysis reveals recent genetic introgression from domestic pigs into Northwest European wild boar populations.

Present-day genetic introgression from domestic pigs into European wild boar has been suggested in various studies. However, no hybrids have been identified beyond doubt mainly because available methods were unable to quantify the extent of introgression and rule out natural processes. Genetic introgression from domestic pigs may have far-reaching ecological consequences by altering traits like the reproduction rate or immunology of wild boar. In this study, we demonstrate a novel approach to investigate genetic introgression in a Northwest (NW) European wild boar data set using a genome-wide single nucleotide polymorphism (SNP) assay developed for domestic pigs. We quantified the extent of introgression using allele frequency spectrum analysis, in silico hybridization simulations and genome distribution patterns of introgressed SNPs. Levels of recent introgression in the study area were expected to be low, as pig farming practices are prevailingly intensive and indoors. However, evidence was found for geographically widespread presence of domestic pig SNPs in 10% of analysed wild boar. This was supported by the identification of two different pig mitochondrial DNA haplotypes in three of the identified hybrid wild boar, suggesting that introgression had occurred from multiple sources (pig breeds). In silico hybridization simulations showed that the level of introgression in the identified hybrid wild boar is equivalent to first-generation hybrids until fifth-generation backcrosses with wild boar. The distribution pattern of introgressed SNPs supported these assignments in four of nine hybrids. The other five hybrids are considered advanced-generation hybrids, resulting from interbreeding among hybrid individuals. Three of nine hybrids were genetically associated with a different wild boar population than the one in which they were sampled. This discrepancy suggests that genetic introgression has occurred through the escape or release of an already hybridized farmed wild boar stock. We conclude that genetic introgression from domestic pigs into NW European wild boar populations is more recent and more common than expected and that genome-wide SNP analysis is a promising tool to quantify recent hybridization in free-living populations.

Volumetry of [¹¹C]-methionine positron emission tomographic uptake as a prognostic marker before treatment of patients with malignant glioma.

The purpose of this positron emission tomography (PET) study was to compare the prognostic value of pretreatment volume of ¹¹C]-methionine (MET) uptake and semiquantitative MET uptake ratio in patients with malignant glioma. The study population comprised 40 patients with malignant glioma. Pretreatment magnetic resonance imaging (MRI) and MET-PET imaging were performed before the initiation of glioma treatment in all patients. The pretreatment MET uptake ratios and volumes were assessed. To create prognostically homogeneous subgroups, patients' pretreatment prognostic factors were stratified according to the six classes of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA). Univariate and multivariate analyses were performed to determine significant prognostic factors. Survival analyses identified the pretreatment volume of MET uptake and a higher RTOG RPA class as significant predictors. In contrast, pretreatment maximum areas of contrast enhancement on MRI and semiquantitative MET uptake ratios could not be identified as significant prognostic factors. The patients' outcomes and Karnofsky Performance Scale scores were significantly correlated with pretreatment volume of MET uptake but not with semiquantitative MET uptake ratio. The data suggest that pretreatment volumetry of MET uptake but not the semiquantitative MET uptake ratio is a useful biologic prognostic marker in patients with malignant glioma.

11C-Methionine positron emission tomographic imaging of biologic activity of a recurrent glioblastoma treated with stereotaxy-guided laser-induced interstitial thermotherapy.

In patients with recurrent glioblastoma multiforme (GBM), local minimally invasive treatment modalities have gained increasing interest recently because they are associated with fewer side effects than open surgery. For example, local tumor coagulation by laser-induced interstitial thermotherapy (LITT) is such a minimally invasive technique. We monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value.

Imaging of non- or very subtle contrast-enhancing malignant gliomas with [¹¹C]-methionine positron emission tomography.

In patients with World Health Organization (WHO) grade III glioma with a lack of or minimal (< 1 cm3) magnetic resonance imaging (MRI) contrast enhancement, the volume of the metabolically active part of the tumor was assessed by [¹¹C]-methionine positron emission tomography (MET-PET). Eleven patients with WHO grade III gliomas underwent MET-PET and MRI (contrast-enhanced T1- and T2-weighted images). To calculate the volumes in cubic centimeters, threshold-based volume of interest analyses of the metabolically active tumor (MET uptake index ≥ 1.3), contrast enhancement, and the T2 lesion were performed after coregistration of all images. In all patients, the metabolically active tumor volume was larger than the volume of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) enhancement (20.8 ± 18.8 vs 0.29 ± 0.25 cm3; p < .001). With the exception of one patient, the volumes of contrast enhancement were located within the metabolically active tumor volume. In contrast, in the majority of patients, MET uptake overlapped with the T2 lesion and reached beyond it (in 10 of 12 MRIs/MET-PET scans). The present data suggest that in patients with WHO grade III glioma with minimal or a lack of contrast enhancement, MET-PET delineates metabolically active tumor tissue. These findings support the use of combined PET-MRI with radiolabeled amino acids (eg, MET) for the delineating of the true extent of active tumor in the diagnosis and treatment planning of patients with gliomas.

Decreased tumor surveillance in perforin-deficient mice.

Immune surveillance against tumors usually depends on T cell recognition of tumor antigens presented by major histocompatibility complex (MHC) molecules, whereas MHC class I- tumors may be controlled by natural killer (NK) cells. Perforin-dependent cytotoxicity is a major effector function of CD8+ MHC class I-restricted T cells and of NK cells. Here, we used perforin-deficient C57BL/6 (PKO) mice to study involvement of perforin and Fas ligand in tumor surveillance in vivo. We induced tumors in PKO and normal C57BL/6 mice by (a) injection of different syngeneic tumor cell lines of different tissue origin in naive and primed mice; (b) administration of the chemical carcinogens methylcholanthrene (MCA) or 12-O-tetradecanoylphorbol-13-acetate (TPA) plus 7,12-dimethylbenzanthracene (DMBA), or (c) by injection of acutely oncogenic Moloney sarcoma virus. The first set of models analyzes the defense against a tumor load given at once, whereas the last two sets give information on immune defense against tumors at the very moment of their generation. Most of the tumor cell lines tested were eliminated 10-100-fold better by C57BL/6 mice in an unprimed situation; after priming, the differences were more pronounced. Lymphoma cells transfected with Fas were controlled 10-fold better by PKO and C57BL/6 mice when compared to untransfected control cells, indicating some role for FasL in tumor control. MCA-induced tumors arose more rapidly and with a higher incidence in PKO mice compared to C57BL/6 or CD8-deficient mice. DMBA+TPA-induced skin papillomas arose with similar high incidence and comparable kinetics in both mouse strains. C57BL/6 and PKO mice have a similar incidence of Moloney murine sarcoma and leukemia virus-induced sarcomas, but tumors are larger and regression is retarded in PKO mice. Thus, perforin-dependent cytotoxicity is not only a crucial mechanism of both cytotoxic T lymphocyte- and NK-dependent resistance to injected tumor cell lines, but also operates during viral and chemical carcinogenesis in vivo. Experiments addressing the role of Fas-dependent cytotoxicity by studying resistance to tumor cell lines that were stably transfected with Fas neither provided evidence for a major role of Fas nor excluded a minor contribution of Fas in tumor surveillance.

Patient-tailored, imaging-guided, long-term temozolomide chemotherapy in patients with glioblastoma.

We present two patients with glioblastoma with an unusually stable clinical course and long-term survival who were treated after surgery and radiotherapy with adjuvant temozolomide (TMZ) chemotherapy for 17 and 20 cycles, respectively. Afterward, adjuvant TMZ chemotherapy was discontinued in one patient and the dosage of TMZ was reduced in the other. In addition to clinical status and magnetic resonance imaging, the biologic activity of the tumors was monitored by repeated methyl-11C-l-methionine (MET) and 3'-deoxy-3'-18F-fluorothymidine (FLT) positron emission tomography (PET) studies in these patients. In these patients, repeated MET- and FLT-PET imaging documented complete response to the initial treatment regimen, including resection, radiation, and TMZ, and during the course of the disease, recurrent, uncontrollable tumor activity. Continuation or dose escalation of TMZ in both patients was shown to be ineffective to overcome the metabolic activity of the tumor. Our data suggest that repeated MET- and FLT-PET imaging provide information on the biologic activity of a tumor that is highly useful to monitor and detect changes in activity.

Volumetry of [(11)C]-methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme.

PURPOSE: We investigated the relationship between three-dimensional volumetric data of the metabolically active tumour volume assessed using [(11)C]-methionine positron emission tomography (MET-PET) and the area of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) enhancement assessed using magnetic resonance imaging (MRI) in patients with recurrent glioblastoma (GBM). MATERIAL AND METHODS: MET-PET and contrast-enhanced MRI with Gd-DTPA were performed in 12 uniformly pretreated patients with recurrent GBM. To calculate the volumes in cubic centimetres, a threshold-based volume-of-interest (VOI) analysis of the metabolically active tumour volume (MET uptake indexes of > or = 1.3 and > or = 1.5) and of the area of Gd-DTPA enhancement was performed after coregistration of all images. RESULTS: In all patients, the metabolically active tumour volume as shown using a MET uptake index of > or = 1.3 was larger than the volume of Gd-DTPA enhancement (30.2 + or - 22.4 vs. 13.7 + or - 10.6 cm(3); p = 0.04). Metabolically active tumour volumes as shown using MET uptake indexes of > or =1.3 and > or = 1.5 and the volumes of Gd-DTPA enhancement showed a positive correlation (r = 0.76, p = 0.003, for an index of > or =1.3, and r = 0.74, p = 0.005, for an index of > or =1.5). CONCLUSION: The present data suggest that in patients with recurrent GBM the metabolically active tumour volume may be substantially underestimated by Gd-DTPA enhancement. The findings support the notion that complementary information derived from MET uptake and Gd-DTPA enhancement may be helpful in developing individualized, patient-tailored therapy strategies in patients with recurrent GBM.

[11C]-L-methionine positron emission tomography in the management of children and young adults with brain tumors.

Only a few Methyl-[11C]-L-methionine (MET) positron emission tomography (PET) studies have focused on children and young adults with brain neoplasm. Due to radiation exposure, long scan acquisition time, and the need for sedation in young children MET-PET studies should be restricted to this group of patients when a decision for further therapy is not possible from routine diagnostic procedures alone, e.g., structural imaging. We investigated the diagnostic accuracy of MET-PET for the differentiation between tumorous and non-tumorous lesions in this group of patients. Forty eight MET-PET scans from 39 patients aged from 2 to 21 years (mean 15 +/- 5.0 years) were analyzed. The MET tumor-uptake relative to a corresponding control region was calculated. A receiver operating characteristic (ROC) was performed to determine the MET-uptake value that best distinguishes tumorous from non-tumorous brain lesions. A differentiation between tumorous (n = 39) and non-tumorous brain lesions (n = 9) was possible at a threshold of 1.48 of relative MET-uptake with a sensitivity of 83% and a specificity of 92%, respectively. A differentiation between high grade malignant lesions (mean MET-uptake = 2.00 +/- 0.46) and low grade tumors (mean MET-uptake = 1.84 +/- 0.31) was not possible. There was a significant difference in MET-uptake between the histologically homogeneous subgroups of astrocytoma WHO grade II and anaplastic astrocytoma WHO grade III (P = 0.02). MET-PET might be a useful tool to differentiate tumorous from non-tumorous lesions in children and young adults when a decision for further therapy is difficult or impossible from routine structural imaging procedures alone.

Characterization of pseudorabies virus of wild boar origin from Europe.

Pseudorabies virus (PrV) infections appear to be more widely distributed in the European wild boar (Sus scrofa) population than assumed. In Europe, attempts to isolate and characterize the causative agents have been limited so far. We therefore collected and examined a total of 35 PrV isolates obtained from wild boar or hunting dogs in Germany, France, Spain, Italy, Slovakia and Hungary between 1993 and 2008. Restriction enzyme analysis of genomic DNA using BamHI showed that all isolates, except one, belonged to genogroup I but different subtypes were evident. For further investigations of the phylogenetic relationships, a 732-bp fragment of the glycoprotein C (gC) gene was amplified by PCR. Sequence analysis revealed about 40 variant positions within this fragment. Comparison of the nucleotide sequences supported the separation into a clade containing isolates from North-Rhine Westphalia, Rhineland-Palatinate (Germany), France and Spain (clade B) and an apparently more variable clade comprising isolates from Brandenburg, Baden-Wurttemberg, Saxony, Saxony-Anhalt (Germany), Slovakia, Hungary, Italy and France (clade A).

Heat-related side-effects of neurological and non-neurological medication may increase heatwave fatalities.

BACKGROUND: During the 2003 French heatwave 15,000 excess deaths were registered. One fifths died from the combination of dehydration, heatstroke, and hyperthermia and one tenth from dehydration, despite abundant water. METHODS AND RESULTS: We hypothesized that physiologic adaptation to heat was not effective in the victims attributable to side-effects of drugs (impaired thermoregulation, suppressed thirst) many of these patients were taking. This could explain why many victims died of dehydration despite availability of water. As a consequence of the global climate change heatwaves may occur more frequently and may be more intense, with a strong impact on the future selection of drugs in elderly patients. CONCLUSION: Insufficient water intake, impaired thermoregulation, and resulting death may be directly linked to the use of certain drugs, implying an immediate need for public awareness during heatwaves and for long-term strategies to mitigate the expected increase in future heatwave-related fatalities.

Molecular imaging-guided gene therapy of gliomas.

Gene therapy of patients with glioblastoma using viral and non-viral vectors, which are applied by direct injection or convection-enhanced delivery (CED), appear to be satisfactorily safe. Up to date, only single patients show a significant therapeutic benefit as deduced from single long-term survivors. Non-invasive imaging by PET for the identification of viable target tissue and for assessment of transduction efficiency shall help to identify patients which might benefit from gene therapy, while non-invasive follow-up on treatment responses allows early and dynamic adaptations of treatment options. Therefore, molecular imaging has a critical impact on the development of standardised gene therapy protocols and on efficient and safe vector applications in humans.

Motor cognition in patients treated with subthalamic nucleus deep brain stimulation: Limits of compensatory overactivity in Parkinson's disease.

Recent fMRI findings revealed that impairment in a serial prediction task in patients suffering from Parkinson's disease (PD) results from hypoactivity of the SMA. Furthermore, hyperactivity of the lateral premotor cortex sustained performance after withdrawal of medication. To further explore these findings, we here examined the impact of deep brain stimulation of the subthalamic nucleus on the activity of the putamen and premotor areas while performing the serial prediction task. To this end, we measured eight male PD patients ON and OFF deep brain stimulation and eight healthy age-matched male controls using [15O] water positron emission tomography to measure regional cerebral blood flow. As expected, PD patients showed poorer performance than healthy controls while performance did not differ between OFF and ON stimulation. Hypoactivity of the putamen and hyperactivity of the left lateral premotor cortex was found in patients compared to controls. Lateral premotor hyperactivity further increased OFF compared to ON stimulation and was positively related to task performance. These results confirm that the motor loop's dysfunction has impact on cognitive processes (here: prediction of serial stimuli) in PD. Extending prior data regarding the role of the lateral premotor cortex in cognitive compensation, our results indicate that lateral premotor cortex hyperactivity, while beneficial in moderate levels of impairment, might fail to preserve performance in more severe stages of the motor loop's degeneration.

Direct demonstration of transcallosal disinhibition in language networks.

Neuroimaging studies in right-handed patients with left hemisphere brain lesions have demonstrated a shift of language activity from left to right inferior frontal gyrus (IFG). This shift may be caused by greater right hemisphere dominance before the injury or by reduced inhibitory activity of the injured left hemisphere. We simulated a brain lesion applying transcranial -magnetic stimulation over left IFG in normal subjects, while simultaneously measuring language activity with positron -emission tomography. Interference with transcranial -magnetic stimulation decreased activity in left and increased it in right IFG in all subjects. We thus demonstrate for the first time that a rightward shift of language activity is caused by the brain lesion and not by greater right-hemisphere dominance, thus supporting the hypothesis of reduced transcallosal inhibition.

Oxidative stress related DNA adducts in the liver of female rats fed with sunflower-, rapeseed-, olive- or coconut oil supplemented diets.

Both animal and epidemiological studies support an effect of fatty acid composition in the diet on cancer development, in particular on colon cancer. We investigated the modulating effect of supplementation of the diet of female F344 rats with sunflower-, rapeseed-, olive-, or coconut oil on the formation of the promutagenic, exocyclic DNA adducts in the liver, an organ where major metabolism of fatty acids takes place. 1,N(6)-ethenodeoxyadenosine (etheno-dA), 3,N(4)-ethenodeoxycytidine (etheno-dC) and 1,N(2)-propandodeoxyguanosine from 4-hydroxy-2-nonenal (HNE-dGp) were determined as markers for DNA-damage derived from lipid peroxidation products and markers for oxidative stress. 8-Oxo-deoxyguanosine (8-Oxo-dG) was also measured as direct oxidative stress marker. The body weight of the rats was not influenced by the four diets containing the different vegetable oils during the 4-week feeding period. Highest adduct levels of etheno-dC (430 +/- 181 adducts/10(9) parent bases), HNE-dGp (617 +/- 96 adducts/10(9) parent bases) and 8-Oxo-dG (37,400 +/- 12,200 adducts/10(9) parent bases) were seen in rats on sunflower oil diet (highest linoleic acid content). Highest adducts levels of etheno-dA (133 +/- 113 adducts/10(9) parent bases) were found in coconut oil diet (lowest content of linoleic acid). Weakly positive correlations between linoleic acid content in the four diet groups were only observed for levels of HNE-dGp and 8-Oxo-dG. Neither the diet based on olive oil (which contains mainly oleic acid) nor the diet based on rapeseed oil (containing alpha-linolenic acid) exerted any significant protective effect against oxidative DNA damage. Our results indicate that a high linoleic acid diet may contribute to oxidative stress in the liver of female rats leading to a marginal increase in oxidative DNA-damage.

Plant orthologs of p300/CBP: conservation of a core domain in metazoan p300/CBP acetyltransferase-related proteins.

p300 and CBP participate as transcriptional coregulators in the execution of a wide spectrum of cellular gene expression programs controlling cell differentiation, growth and homeostasis. Both proteins act together with sequence-specific transcription factors to modify chromatin structure of target genes via their intrinsic acetyltransferase activity directed towards core histones and some transcription factors. So far, p300-related proteins have been described in animals ranging from Drosophila and Caenorhabditis elegans to humans. In this report, we describe p300/CBP-like polypeptides in the plant Arabidopsis thaliana. Interestingly, homology between animal and plant p300/CBP is largely restricted to a C-terminal segment, about 600 amino acids in length, which encompasses acetyltransferase and E1A-binding domains. We have examined whether this conservation in sequence is paralleled by a conservation in function. The same amino acid residues critical for acetyltransferase activity in human p300 are also critical for the function of one of the plant orthologs. Remarkably, plant proteins bind to the adenovirus E1A protein in a manner recapitulating the binding specificity of mammalian p300/CBP. The striking conservation of an extended segment of p300/CBP suggests that it may constitute a functional entity fulfilling functions that may be essential for all metazoan organisms.

Induction of cell proliferation in the forestomach of F344 rats following subchronic administration of styrene 7,8-oxide and butylated hydroxyanisole.

The question addressed was whether stimulation of cell proliferation could be responsible for tumor induction in the forestomach by styrene 7,8-oxide (SO). Male F344 rats were treated for 4 weeks with 0, 137, 275, and 550 mg/kg SO by p.o. gavage 3 times/week. Positive controls received 0, 0.5, 1, and 2% butylated hydroxyanisole (BHA) in the diet for 4 weeks. Twenty-four h before termination of the experiment, the rats were implanted s.c. with an osmotic minipump delivering 5-bromo-2'-deoxyuridine (BrdU). Cell proliferation in the forestomach was assessed by immunohistochemistry for BrdU incorporated into DNA. Cell number/mm section length and fraction of replicating cells (labeling index) were determined in 3 domains of the forestomach, the saccus caecus, the midregion, and the prefundic region. With the exception of the prefundic region of the low-dose SO group, a significant increase of the labeling index was found in all regions both with SO and BHA. Rats treated with BHA showed, in addition, a dose-dependent increase in number and size of hyperplastic lesions. This was most pronounced in the prefundic region where carcinomas were reported to be localized. In this region, the number of dividing cells/mm section length was increased up to 17-fold. With SO, only marginal morphological changes were occasionally observed, despite the fact that the respective long-term treatment had been reported to result in a higher carcinoma incidence than treatment with BHA. It is concluded that the rate of replicating cells alone, numerically expressed by the labeling index, is an insufficient tool for interpreting the role of cell division in carcinogenesis. It is postulated that SO and BHA induce forestomach tumors via different mechanisms. While hyperplasia in the prefundic region most likely dominates the carcinogenicity of BHA, a mechanism combining marginal genotoxicity with strong promotion by increased cell proliferation appears to be involved in the tumorigenic action of SO.

Nonlinear dose-response relationship for the binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo.

With radioactive compounds of high specific activity, the binding of carcinogens to DNA can be measured with doses that are ineffective in long-term studies. The binding of tritiated benzo(a)pyrene to liver DNA of adult male rats has been determined 50 hr after a single i.p. injection of doses between 40 microgram/kg and 4 mg/kg. The dose-response relationship is linear up to 1 mg/kg, shows a step towards 2 mg/kg, and gives a shallow linear slope above that value. The observed binding ranges from 1.7 to 180 nmoles benzo(a)pyrene per mole DNA phosphate. The nonlinearity could be due to an induction of metabolizing enzymes. The microsomal aryl hydrocarbon hydroxylase activity increases significantly 24 hr after a single dose of 4 mg/kg and 48 hr after doses of 2 and 4 mg/kg, but no induction is found with 1 mg/kg. The binding from an equimolar dose is 35 times lower than the one found on mouse skin DNA and 300 times lower than that of N,N-dimethylnitrosamine in rat liver. A good correlation exists to the respective tumor formation in long-term studies.

Daily affect dynamics predict early response in CBT: Feasibility and predictive validity of EMA for outpatient psychotherapy.

BACKGROUND: Previous studies have shown that individual differences in affect dynamics during depressed patients' everyday lives allow the prediction of treatment outcome and of symptom reoccurrence in remitted patients. In this study, we analyze whether understanding patients' affective states and their fluctuation patterns helps predict early treatment response (until session 5). METHODS: Ecological Momentary Assessment (EMA) strategies allow in-depth analyses of real-time affective states and of their dynamics. Repeated assessments were made four times a day during a two-week period to capture real-life affective states (positive affect, PA and negative affect, NA) and dynamics (fluctuations in NA and PA) before the start of outpatient treatment of 39 patients. Due to the nested structure of the data, hierarchical linear models were conducted. RESULTS: PA/NA ratios, as well as fluctuations in NA predicted early treatment response, even when adjusting for initial impairment. In contrast, mean levels of NA or PA, as well as fluctuations in PA did not predict treatment response. LIMITATIONS: The time between the EMA assessment and treatment onset varied between patients. However, this variation was not associated with early change. CONCLUSIONS: The results suggest that pre-treatment affect dynamics could provide valuable information for predicting treatment response independent of initial impairment levels. Better predictions of early treatment response help to improve treatment choices early in the treatment progress.

In vivo regulation of single copy and amplified N-myc in human neuroblastoma cells.

Amplification with subsequent overexpression of N-myc is a recurrent genomic alteration of neuroblastoma cells. DMS-in-vivo-footprinting of the basal promoter of the human N-myc gene (positions -221 to +21) revealed three changes in promoter architecture that are clustered in a 50 bp region and included (1) protein binding to two overlapping E2F-sites, (2) extreme hypersensitivity of guanine - 159, and (3) a short stretch of single stranded DNA with a single protected guanine. While in transient assays the basal promoter activated gene expression in all cell lines analysed, the changes at the endogenous promoter were restricted to neuroblastoma cells with strong N-myc expression. The hypersensitivity of guanine -159 could result from protein binding to a flanking, evolutionary conserved 5'-CCTCCC-3'-element, referred to as CT-box, that was bound in vitro in a Zn2+-requiring manner by a protein from nuclear extracts of neuroblastoma cells. Four copies of the CT-box in front of an N-myc minimal promoter (-60 to + 18) activated expression of a reporter gene in transient transfections whereas four copies of the mutant element did not. Our data add N-myc to a growing list of mammalian genes with CT-boxes that bind proteins in a Zn2+-dependent manner. Moreover, the data suggest that a common mechanism controls N-myc expression in neuroblastomas irrespective of N-myc copy number, and that in cell lines with amplification all gene copies contribute to N-myc expression.