Attenuated prefrontal activation during decision-making under uncertainty in schizophrenia: a multi-center fMRI study.

Decisions are called decisions under uncertainty when either prior information is incomplete or the outcomes of the decision are unclear. Alterations in these processes related to decisions under uncertainty have been linked to delusions. In patients with schizophrenia, the underlying neural networks have only rarely been studied. We aimed to disentangle the neural correlates of decision-making and relate them to neuropsychological and psychopathological parameters in a large sample of patients with schizophrenia and healthy subjects. Fifty-seven patients and fifty-seven healthy volunteers from six centers had to either indicate via button-press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or indicate whether eight red balls had been presented (baseline condition) while BOLD signal was measured with fMRI. Patients based their decisions on less conclusive evidence and had decreased activations in the underlying neural network, comprising of medial and lateral frontal as well as parietal areas, as compared to healthy subjects. While current psychopathology was not correlated with brain activation, positive symptoms led to longer decision latencies in patients. These results suggest that decision-making under uncertainty in schizophrenia is affected by a complex interplay of aberrant neural activation. Furthermore, reduced neuropsychological functioning in patients was related to impaired decision-making and task performance was modulated by distinct positive symptoms.

Investigation of decision-making under uncertainty in healthy subjects: a multi-centric fMRI study.

Decision-making is an everyday routine that entails several subprocesses. Decisions under uncertainty occur when either prior information is incomplete or the outcomes of the decision are unclear. The aim of the present study was to disentangle the neural correlates of information gathering as well as reaching a decision and to explore effects of uncertainty acceptance or avoidance in a large sample of healthy subjects. Sixty-four healthy volunteers performed a decision-making under uncertainty task in a multi-center approach while BOLD signal was measured with fMRI. Subjects either had to indicate via button press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or they had to indicate whether 8 red balls had been presented (baseline condition). During the information gathering phase (contrasted against the counting phase) a widespread network was found encompassing (pre-)frontal, inferior temporal and inferior parietal cortices. Reaching a decision was correlated with activations in the medial frontal cortex as well as the posterior cingulate and the precuneus. Effects of uncertainty acceptance were found within a network comprising of the superior frontal cortex as well as the insula and precuneus while uncertainty avoidance was correlated with activations in the right middle frontal cortex. The results depict two distinct networks for information gathering and the indication of having made a decision. While information-gathering networks are modulated by uncertainty avoidance and - acceptance, underlying networks of the decision itself are independent of these factors.

[Biomarker screening for early detection of cancer]. / Sinn und Unsinn von Tumormarkern in der Krebsfrüherkennung.

The question of when a certain concentration of a serum biomarker turns into a tumor marker, i. e. an objectively verifiable criterion for tumor diagnosis, leads to the analysis of the specificity (a measure of the proportion of correctly identified healthy individuals), sensitivity (a measure of the proportion of correctly recognized cancer patients), and precision (positive predictive value). Or in short: a tumor marker is specific if no healthy individual has one. This constitutes the problem: The serum concentrations of biomarkers of cancer patients and healthy subjects overlap. Healthy individuals occasionally have "tumor markers" and cancer patients in turn sometimes express inconspicuous biomarkers.

[Early onset psychosis: rationale and concept of a cognitive-behavioral intervention]. / Jugendliche mit psychotischen Störungen: Rationale und Konzept einer kognitiv-verhaltenstherapeutischen Intervention.

Early onset psychoses (EOP, age of onset between age 14 and 18 years) are known to be associated with a poorer outcome than adult onset psychoses, both in terms of psychotic symptoms and social remission. For adult patients with psychosis, numerous cognitive-behavioral interventions have proven their effectiveness in recent years. This contrasts with a dearth of findings for EOP, even though it can be considered as a variant of adult onset psychosis. Thus, we have developed a cognitive-behavioral therapy intervention that was specifically adapted to the characteristics and needs of young people suffering from psychosis. The concept of the intervention is outlined in the present article. Acceptability and feasibility of the intervention are currently undergoing evaluation in a randomised, controlled pilot study.

Evaluation of a cognitive behaviourally oriented service for relapse prevention in schizophrenia.

OBJECTIVE: There is little work demonstrating the effectiveness of cognitive behaviourally oriented interventions in routine service settings. This pragmatic trial is designed to test the impact of a group treatment service on relapse rates under the conditions of routine health care. METHOD: A total of 169 schizophrenia patients were randomly allocated either to a comprehensive cognitive behaviourally oriented service (CBOS) or to treatment as usual (TAU). The primary outcome is the time until the first relapse after discharge from hospital. Relapse was defined as an increase in positive or negative symptoms as assessed with the Positive and Negative Syndrome Scale. Survival analysis has been conducted up to the 6-month assessment. RESULTS: The mean time to relapse after discharge from hospital in the CBOS group was significantly longer than in the TAU group (log rank test, P = 0.033). This was due to less exacerbations regarding negative symptoms in the CBOS condition (log rank test, P = 0.014). The number of social contacts was improved in the CBOS group only. CONCLUSION: The CBOS intervention appears to be beneficial in reducing early negative symptom exacerbations.

The antimicrobial effect of acetic acid--an alternative to common local antiseptics?

Acetic acid has been commonly used in medicine for more than 6000 years for the disinfection of wounds and especially as an antiseptic agent in the treatment and prophylaxis of the plague. The main goal of this study was to prove the suitability of acetic acid, in low concentration of 3%, as a local antiseptic agent, especially for use in salvage procedures in problematic infections caused by organisms such as Proteus vulgaris, Acinetobacter baumannii or Pseudomonas aeruginosa. This study was designed to compare the in vitro antimicrobial effect of acetic acid with those of common local antiseptics such as povidone-iodine 11% (Betaisodona), polyhexanide 0.04% (Lavasept), mafenide 5% and chlohexidine gluconate 1.5% cetrimide 15% (Hibicet). Former studies suggest the bactericidal effect of acetic acid, but these data are very heterogeneous; therefore, a standardised in vitro study was conducted. To cover the typical bacterial spectrum of a burn unit, the following Gram-negative and Gram-positive bacterial strains were tested: Escherichia coli, P. vulgaris, P. aeruginosa, A. baumannii, Enterococcus faecalis, Staphylococcus epidermidis, methicillin-resistant Staphylococcus aureus (MRSA) and beta-haemolytic Streptococcus group A and B. The tests showed excellent bactericidal effect of acetic acid, particularly with problematic Gram-negative bacteria such as P. vulgaris, P. aeruginosa and A. baumannii. The microbiological spectrum of acetic acid is wide, even when tested at a low concentration of 3%. In comparison to our currently used antiseptic solutions, it showed similar - in some bacteria, even better - bactericidal properties. An evaluation of the clinical value of topical application of acetic acid is currently underway. It can be concluded that acetic acid in a concentration of 3% has excellent bactericidal effect and, therefore, seems to be suitable as a local antiseptic agent, but further clinical studies are necessary.

Three-year follow-up of a patient with early-onset Alzheimer's disease with presenilin-2 N141I mutation - case report and review of the literature.

Autosomal dominant early-onset Alzheimer disease (EOAD) is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. Mutation analysis of the APP, PSEN1 and PSEN2 genes was performed. We herein report the case of a German EOAD patient with a family history of dementia and a missense mutation at codon 141 (N141I) of the PSEN2 gene. To our knowledge, this is the first German EOAD patient without a Volga-German ancestry and a positive family history for dementia carries the mutation PSEN-2 N141I. The patient came to our clinic for the first time when she was 47 years old. During the following 3 years, her Mini-Mental State Examination (MMSE) score dropped from 28 to 0. Mild cognitive impairment (MCI) was an early symptom that was already present during the first consultation. The concentration in cerebrospinal fluid (CSF) of tau-protein (1151 pg/ml) was increased, whereas the concentration of beta-amyloid protein (Abeta1-42) was decreased (335 pg/ml). Magnetic resonance imaging (MRI) revealed only slight changes in the early stage of the disease and positron emission tomography with (18F) fluoro-2-deoxy-D-glucose (18F-FDG PET) demonstrated glucose reduction left parietal and in the precuneus region. Follow-up MRI and 18F-FDG PET studies showed progression of atrophy of the left entorhinal cortex with relative sparing of the hippocampus and progressive hypometabolism of both temporoparietal lobes and left frontal lobe.

[Familial Alzheimer's disease with presenilin 2 N141I mutation. A case report]. / Familiäre Alzheimer-Demenz mit Präsenilin 2 N141I Mutation. Eine klinische Falldarstellung

Alzheimer's disease (AD) is the most common form of dementia. Approximately 0.5 per cent of all AD is caused by single major gene mutations and autosomal dominant inheritance. These familial types with early-onset (EOFAD) usually display dementia before the age of 60. Such mutations have been found in the gene encoding amyloid precursor protein (APP), and in the genes encoding presenilin 1 (PSEN1) or presenilin 2 (PSEN2). We herein report the case of a German patient with a EOFAD and a missense mutation at codon 141 (N141I) of the PSEN2 gene. The patient came to our psychiatric clinic for the first time when she was 49 years old. During the following 3 years, her Mini-Mental-State-Examination (MMSE) score dropped from 14 to 0 points. Positron emission tomography with [18F] Fluorodeoxyglucose (18F-FDG PET) demonstrated glucose reduction left parietal and in the pre-cuneus region. Follow-up 18F-FDG PET studies showed progressive hypometabolism of both temporoparietal lobes and left frontal lobe.

Sulfate assimilation in basal land plants - what does genomic sequencing tell us?

Sulfate assimilation is a pathway providing reduced sulfur for the synthesis of cysteine, methionine, co-enzymes such as iron-sulfur centres, thiamine, lipoic acid, or Coenzyme A, and many secondary metabolites, e.g., glucosinolates or alliins. The pathway is relatively well understood in flowering plants, but very little information exists on sulfate assimilation in basal land plants. Since the finding of a putative 3'-phosphoadenosine 5'-phosphosulfate reductase in PHYSCOMITRELLA PATENS, an enigmatic enzyme thought to exist in fungi and some bacteria only, it has been evident that sulfur metabolism in lower plants may substantially differ from seed plant models. The genomic sequencing of two basal plant species, the Bryophyte PHYSCOMITRELLA PATENS, and the Lycophyte SELAGINELLA MOELLENDORFFII, opens up the possibility to search for differences between lower and higher plants at the genomic level. Here we describe the similarities and differences in the organisation of the sulfate assimilation pathway between basal and advanced land plants derived from genome comparisons of these two species with ARABIDOPSIS THALIANA and ORYZA SATIVA, two seed plants with sequenced genomes. We found differences in the number of genes encoding sulfate transporters, adenosine 5'-phosphosulfate reductase, and sulfite reductase between the lower and higher plants. The consequences for regulation of the pathway and evolution of sulfate assimilation in plants are discussed.

Comparison between tympanic and anal temperature with a clinical infrared ray thermometer in dogs / Comparação entre a temperatura timpânica e a temperatura anal usando um termômetro clínico de raio infravermelho em cães

A clinical thermometer of infrared rays was used twice to record consecutively the temperature of the tympanic membrane in each ear and in the anus of 53 dogs. Temperatures did not differ significantly between organs, and were strongly correlated. The anal temperature measurement with an infrared thermometer in dogs is feasible and trustworthy, as well as the thermal checking of tympanic temperature.

Utilizou-se um termômetro clínico de emissão de raios infravermelhos para medir, duas vezes consecutivas, a temperatura da membrana timpânica de cada ouvido e duas vezes a temperatura no ânus de 53 cães. Não houve diferença entre as temperaturas quanto ao órgão estudado e a correlação entre as temperaturas foi alta. Em cães, a medida da temperatura anal com o termômetro clínico de emissão de raios infravermelhos é rápida e confiável tanto quanto a da temperatura timpânica.

[Evaluation of the therapeutic benefit of 41.8 degrees C whole body hyperthermia plus ifosfamide, carboplatin and etoposide (ICE) for patients with malignant pleural mesothelioma using the Modified Brunner-Score (MBS)]. / Bewertung des therapeutischen Gewinns von Patienten mit Pleuramesotheliom unter Therapie mit 41,8 degrees C Ganzkörperhyperthermie plus Ifosfamid, Carboplatin und Etoposid (ICE) anhand des Modifizierten Brunner-Score (MBS).

BACKGROUND: We performed a phase-II-study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i. e., ifosfamide (5 g/m (2) on day 1), carboplatin (300 mg/m (2) on day 1) and etoposide (150 mg/m (2) on days 2 and 3), administered every 4 weeks, to assess the treatment benefit for patients with malignant pleural mesothelioma. To date this is mainly done by measurement of response rates and overall survival, as it can be widely found in the literature. In fewer cases there is also a quality of life assessment. Here we describe an instrument well-capable for a more comprehensive statement on the therapeutic benefit by linking several study end points including quality of life assessment, the Modified Brunner-Score (MBS). MATERIAL AND METHODS: The Modified Brunner Score (MBS) was used for this assessment. MBS integrates progression free survival, change of physical performance (WHO-index), a quality of life self-assessment by the patient and toxicity. A positive score means a therapy benefit and vice versa. RESULTS AND CONCLUSIONS: Of 27 chemonäive, non-metastatic patients enrolled, 22 were evaluable for assessment. Overall survival and progression free survival for all patients was 76 weeks (95 % CI 65.4 weeks - 87.8 weeks) and 29.6 weeks (95 % CI 24.4 weeks - 34.7 weeks) respectively. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia and affection of the GI tract, like mucositis, nausea and vomiting. Mean Improvement of Performance Index (WHO) was 0.29 points. The MBS showed a score of 4.21 points (- 4.43 - 16.45 range) for the overall study group. 16 of 22 evaluable patients achieved a positive score. MBS is a suitable tool to evaluate the treatment benefit especially in non-standard therapy approaches. For WBH plus ICE, it showed a beneficial effect on overall quality of life in the majority of patients.

A Systemic Hyperthermia Oncologic Working Group trial. Ifosfamide, carboplatin, and etoposide combined with 41.8 degrees C whole-body hyperthermia for metastatic soft tissue sarcoma.

BACKGROUND: Based on earlier clinical and preclinical studies, we conducted a phase II trial in metastatic sarcoma patients of the combination of 41.8 degrees C (x60 min) radiant heat (Aquatherm) whole-body hyperthermia (WBH) with 'ICE' chemotherapy. The ICE regimen consists of ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (100 mg/m(2)), concurrent with WBH, with etoposide also on days 2 and 3 post-WBH. METHODS: Therapy was delivered every 4 weeks for a maximum of 4 cycles. All patients received filgrastim or lenograstim. RESULTS: Of 108 patients enrolled as of September 2001, 95 are evaluable for response. Of the evaluable patients (mean ECOG performance status approximately 1; mean age 42.3; 58% male) 33 had no prior therapy for metastatic disease, and 62 were pretreated (mean: 1.5 prior regimens). The overall response rate was 28.4% (4 complete remissions and 23 partial remissions) with stable disease (SD) in 31 patients. For no prior therapy, the response rate was 36%; in pretreated patients it was 24%. The median overall survival by Kaplan-Meier estimates was 393 days (95% CI 327, 496); the median time to treatment failure was 123 days (95% CI 77, 164). The major toxicity (287 cycles) was grade 3 or 4 neutropenia and thrombocytopenia seen in 79.7 and 60.6% of treatments respectively; there were 7 episodes of infection (grade 3/4) with 2 treatment-related deaths, bot involving disease progression and ureteral obstruction. CONCLUSION: These results are consistent with continued clinical investigation of this combined modality approach.

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.

We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated.

[Psychotherapy of positive symptoms in the treatment of patients with schizophrenia psychosis]. / Psychotherapie produktiver Symptomatik bei Patienten mit schizophrener Psychose.

While the treatment of positive symptoms of patients with schizophrenic psychosis appeared until recently to be solely pharmacotherapeutic, new research findings show the efficacy of cognitive-behavioural psychotherapy (CBT) on positive symptoms in chronic psychotic patients. In addition, the effectiveness even in acute and recent-onset psychosis could be shown in some studies. The effects of CBT and standard care in psychosis compared to standard care alone and to other psychosocial interventions plus standard care are reviewed. The results of several studies and one meta-analysis show that CBT in schizophrenia patients has a direct effect on psychotic symptoms such as hallucinations as well as on relapse prevention. In routine settings,however,CBT has until now only rarely been delivered to these patients. In so-called large pragmatic trials, which might be subsumed as phase IIIb studies, the effects are tested. The therapeutic approach with the components of CBT for psychosis are described: building a therapeutic relationship, cognitive-behavioural coping strategies, developing an understanding of the experience of psychosis,working on hallucinations and delusions, addressing negative self-evaluations, anxiety, and depression,managing risk of relapse and social disability. Further clinical implications are described (capability of learning the therapeutic strategies, deliverability in broader clinical settings, acceptability by patients, combination with atypical neuroleptic drugs,and treatment of choice in risk populations).

Invasiveness of human pleural mesothelioma cells is influenced in vitro by the three-dimensional structure of the ECM and its composition.

The grade of malignancy of a neoplasm is influenced by the invasive and metastatic potential of the tumor cells. The extracellular matrix of tissues is known to interact with many aspects of the biological behavior of tumor cells, such as differentiation and invasiveness. Therefore we studied the influence of the extracellular matrix on the morphology and invasiveness of the human biphasic pleural mesothelioma cell line MSTO-211H in vitro. The major components of the two strata encountered by a pleural mesothelioma cell leaving the epithelial community were mimicked by plating cells either on collagen I, the major component of the underlying stratum fibrosum, being encountered by cells under pathological conditions or on reconstituted basement membrane (Matrigel) in order to simulate the basement membrane of the stratum serosum of the mesothelium, which is the matrix cells have contact to under physiological conditions. Growth on collagen I leads to cell separation and invasion into the matrix, whereas growth of MSTO-211H cells on Matrigel results in the formation of a huge and dense network of cells extending throughout the whole plating area. The morphology of cell contacts between the two populations varies impressively. While cells on collagen I hardly find to each other in groups, and if so, with a broad intercellular cleft, Matrigel induces the tight approach of membranes of neighbouring cells with formation of syncytium-like structures. Administration of the main ECM components laminin and collagen IV alone and together in equimolar concentrations as present in Matrigel, does not result in any morphological changes when compared to cells growing on plastic substrates or on collagen I. Therefore, collagen I increases cell separation and invasiveness whereas an intact basement membrane seems to prevent the cells from separating and spreading, thus lowering their invasive potential.

[Aromatase inhibitors of the 3rd generation. What can the "pill against breast cancer" really do?]. / Aromatasehemmer der dritten Generation. Was kann die "Pille gegen Brustkrebs" wirklich?

Metastatic cancer of the breast in postmenopausal women can be treated with a number of "hormone-active" substances. The drugs of first choice are still anti-estrogens. Today, the three highly selective oral aromatase inhibitors anastrozole, letrozole and exemestane are additionally available for use in continuing progression under anti-estrogen treatment. Roughly one woman in three derives benefit from these new medications as reflected by objective remission or stabilization of the disease for more than 6 months. Neither chemical structure (steroidal/non-steroidal), nor the different nature of inhibition of the active centre of the aromatase, nor whether the inhibition of the enzyme is reversible or irreversible, has any influence on the parameters: response rate, response duration and clinical benefit.

Hyperthermia and mafosfamide in a human-derived malignant pleural mesothelioma cell line.

PURPOSE: Diffuse malignant pleural mesothelioma is the most common primary pleural malignancy. At the beginning of the last century, this tumor was of minor incidence. Meanwhile, the use of asbestos has led to and is still leading to a rise in pleural mesothelioma incidence. There is no standard therapy for this highly aggressive disease and the development of new therapeutic strategies is imperative. METHODS: We, therefore, investigated the morphological and pharmakokinetic effects of a combined thermochemotherapy consisting of the administration of different dosages of mafosfamide with and without the application of a 1-h hyperthermia at 41.7 degrees C on the human biphasic malignant pleural mesothelioma cell line MSTO-211H. After therapy, cells were prepared for light and electron microscopy. BrdU-incorporation for the S-phase fraction, TUNEL-labeling for detection of apoptosis, and quantitative assessments using the MTT assay were performed. RESULTS: Our results demonstrate that the combination of mafosfamide with hyperthermia leads to qualitatively and quantitatively enhanced cellular damage compared to monotherapy. During combined thermochemotherapy, cell damage and death is already induced at lower mafosfamide concentrations than without hyperthermia which suggests an additive effect from hyperthermia to the action of the alkylating drug mafosfamide. Cell death thereby mostly occurs as necrotic cell death rather than as apoptosis, although in a combined thermochemotherapy apoptosis is induced temperature-dependently, when comparing temperatures from 37 degrees C to 43 degrees C. CONCLUSIONS: We suggest that the effect of substances such as ifosfamide and cyclophosfamide which are in clinical use, might be enhanced by the combination of local or regional hyperthermia in order to improve the therapeutical index of these substances in the treatment of pleural mesothelioma.

A priori expectancy bias in patients with panic disorder.

BACKGROUND: Several studies have indicated that phobic participants tend to overassociate fear-relevant stimuli and aversive outcomes, i.e, they show a covariation bias. Such a bias seems to be a powerful way to confirm danger expectations and enhance fear. Therefore, a covariation bias might be an important factor in the maintenance of fear. METHODS: To investigate a covariation bias in patients with panic disorder, we had 29 patients and 29 healthy control participants rate the a priori probabilities with which they would expect pictures of mushrooms, spiders, erotic scenes, and emergency situations to be paired with a tone, shock, or nothing. RESULTS: This is the first study to show that patients with panic disorder specifically overestimate the association between panic-relevant stimuli and a following negative consequence. This distorted contingency expectancy represents a panic-specific covariation bias, since it was not observable for other stimuli-consequence combinations and only to a significantly lesser degree in control participants. CONCLUSIONS: The underpinning hypothesis is that overestimation of threat plays a casual role in the origins and maintenance of anxiety. Thus anxiety may induce a covariation bias, which in turn may enhance the perceived threat, which in turn may intensify the anxiety etc. This reciprocal relationship between covariation bias and anxiety may have clinical implications for prediction and treatment in patients with panic disorder.

Ureteric and pulmonary endometriosis.

Pulmonary lesions and ureter involvement are rare complications of endometriosis. We describe the first case with an involvement of both sites in this condition. The radiographs showed "pulmonary metastases" together with clinical findings of a hydronephrosis, mimicing a malignant metastatic gynecologic tumor of unknown primary. A laparoscopy showed severe endometriotic lesions; therefore the findings were most likely related to the condition of endometriosis. The patient was treated with gosereline acetate for six months (Zoladex). Control radiographs showed complete regression of the pulmonary lesions and the patient is symptom free at 36 months after diagnosis.