Input dysfunction and beyond--an evaluation of CPT components

The aim of our project is to analyze the functional meaning of neurocognitive components of the Continuous Performance Tests (CPT), which may be responsible for the well-documented performance deficit. Since the CPT can be considered as a vulnerability marker for schizophrenia, this question is of special interest. We set up a test battery testing five different cognitive processing modes: perceptual organization, selective attention, short-term memory (storing component), working memory (rehearsal component), and vigilance/sustained attention. In order to avoid the pitfall of interpreting results confounded by psychometric differences within tasks, we created psychometrically parallel versions within each experimental block (following the proposals of Chapman and Chapman [J. Nerv. Ment. Dis. 171 (1983) 658]). At the main experimental session, we tested newly admitted patients with a DSM diagnosis of schizophrenia during remission (N=30), patients with major depressive disorder (MD) (N=18), and healthy controls (N=20). Results showed that differences specific for schizophrenia are seen at the experimental block, which tests perceptual organization. However, all levels of perceptual organization performance were concerned, i.e., from processing organized to non-organized patterns. The regression analysis showed that 3-7 CPT version performances could be explained by problems with short-term memory, sustained attention, and perceptual organization. In light of these findings, we discussed whether etiology of schizophrenia could be conceptualized as a circumscribed neurocognitive deficit or a multifunctional, multilocal deficit.     

Savoxepine versus haloperidol

Savoxepine, an atypical neuroleptic compound developed in the 1980s, was believed to act via selective limbic dopamine D₂-receptor blockade. The results of the presented double-blind, randomised, controlled clinical trial comparing savoxepine (n = 58) with haloperidol (n = 29) did not confirm the preclinical data suggesting that savoxepine would produce fewer extrapyramidal symptoms than the comparator. Animal data and PET-results obtained a posteriori suggested that this unfavourable outcome may have been due to the conventional, step-wise dose increase strategy used in the study leading to a high dopamine D₂-receptor occupancy in the striatum thus eliciting EPS. Using either a slower dose-titration or a high, single loading dose followed by a low maintenance dosing may have offered the possibility to obtain a good antipsychotic effect together with low incidence of EPS. In future clinical trials with new neuroleptics, the preclinical data should be carefully evaluated, and drug brain kinetic parameters taken into consideration. Received: 4 December 2001 / Accepted: 5 April 2002     

Anti-p53 in breast cancer: concordance of different assay procedures and association with p53 antigen expression

OBJECTIVE: Anti-p53 levels detected by different methods were compared in a predefined group of patients with breast cancer and correlated with p53 antigen expression in the corresponding tumors. METHODS: P53 autoantibodies were investigated in 165 patients with primary breast cancer using ELISAs with recombinant or native p53. Immunoblot and indirect immunofluorescence (Huh7) were used for confirmation, p53 antigen expression in the tumor was determined immunohistochemically. RESULTS: Using ELISA, overall 18/165 positives (11%) were detected, with only partly concordant results between the assays. Five positive sera were confirmed by immunoblot, and three also by indirect immunofluorescence. Anti-p53-positive patients detected by more than two assays showed accumulated p53 in the tumor (6/6) and mostly suffered from recurrent tumors (4/6; p = 0.02). In these cases, a trend towards a shortened disease-free interval was found (26 vs. 49 months; n.s.). In patients with a positive or borderline result in only one of the serological methods, there was no increased rate of p53 accumulation compared to anti-p53-negative patients (4/19 versus 35/126). CONCLUSIONS: Lack of assay standardization may partly explain the divergence in reports on anti-p53 and its clinicopathological associations. We speculate that, in different groups of patients, anti-p53 might be induced by different mechanisms.     

Do neuroleptics alter the cerebral intracellular pH value in schizophrenics?-a (31)P-MRS study on three different patient groups

The intracellular pH value has a profound influence on cerebral metabolism. Thus, inadequate pH control may intensify local metabolic deficits. To investigate the influence of neuroleptics on cerebral intracellular pH, we retrospectively evaluated the findings from three independent phosphorous-31 magnetic resonance spectroscopy ((31)P-MRS) studies on schizophrenic patients. A total sample of 72 patients and 32 healthy controls was investigated. A modified pH value was found only in those schizophrenic patients treated with the atypical neuroleptic clozapine.     

Munchhausen patients in general hospitals--Clinical features and treatment approaches in C-L psychiatry settings

Factitious disorders have been reported in 0.5 - 1 % of general hospital patients. It often takes several years until the disorder is detected. During this period, enormous health care cost can arise not least out of iatrogenic self-induced mutilations and related secondary somatic complications. Apart from surgeons and physicians, consultation-liaison (C-L) psychiatrists are particularly called on to diagnose factitious disorders at an early stage in order to avoid unnecessary diagnostic and therapeutic procedures, treatment dropout and doctor shopping. This article gives an overview of clinical features and treatment approaches in C-L psychiatry settings.     

Intraoperative venous blood sampling to localize a small androgen-producing ovarian tumor.

BACKGROUND: Among other causes of virilization, ovarian tumors can be the cause of excessive androgen production. We report the case of a Leydig cell tumor of the ovary where diagnostic attempts to localize the source of hyperandrogenism preoperatively failed owing to relatively small tumor size. CASE: A 36-year-old woman presented with clinical signs of severe virilization including progressive balding, increased hirsutism, secondary amenorrhea and enlargement of the clitoris. Extensive work-up included endocrinological tests, pelvic ultrasound, magnetic resonance imaging, chromosomal analysis, norcholesterol scintigraphy and selective venous sampling, without direct localization of the source of hyperandrogenism. Persistently high plasma testosterone prompted an explorative laparotomy. Intraoperative selective blood sampling of the ovarian veins and palpation gave evidence of a right ovarian tumor, which was then removed. Histological examination revealed the presence of a pure Leydig cell tumor. CONCLUSION: Exploratory laparotomy with intraoperative selective blood sampling of the ovarian veins might be a useful approach in patients without accurate preoperative localization of androgen-producing tumors of the ovaries.     

Tumor-driven paracrine platelet-derived growth factor receptor alpha signaling is a key determinant of stromal cell recruitment in a model of human lung carcinoma.

Activated fibroblasts are thought to play important roles in the progression of many solid tumors, but little is known about the mechanisms responsible for the recruitment of fibroblasts in tumors. Using several methods, we identified platelet-derived growth factor A (PDGFA) as the major fibroblast chemoattractant and mitogen from conditioned medium generated by the Calu-6 lung carcinoma cell line. In addition, we showed that Calu-6 tumors express significant levels of PDGFC, and that the levels of expression of these two PDGFRalpha ligands correlate strongly with the degree of stromal fibroblast infiltration into the tumor mass. The most intense expression of PDGFRalpha was observed in fibroblasts in the tumor outer rim. We subsequently showed that disrupting PDGFRalpha-mediated signaling results in significant inhibition of tumor growth in vivo. Furthermore, analysis of a compendium of microarray data revealed significant expression of PDGFA, PDGFC, and PDGFRalpha in human lung tumors. We propose that therapies targeting this stromal cell type may be effective in treating certain types of solid tumors.     

Variation of the N-acetyltransferase 2 gene in a Romanian and a Kyrgyz population.

As part of a project on environmental disasters in minority populations, this study aimed to evaluate differences in the sequence of N-acetyltransferase 2 (NAT2) as a metabolic susceptibility gene in yet unexplored ethnicities. Eight single nucleotide polymorphisms (SNP) in the NAT2 coding region and a variant in the 3' flanking region were analyzed in 290 unrelated Kyrgyz and 140 unrelated Romanians by SNP-specific PCR analysis. The variants 341C, 481T, and 803G were less and 857A more prevalent in Kyrgyz (P < 0.0001). The variant at site 857 indicates Asian descent. 282C>T and 590G>A showed no significant variation by ethnicity. 364G>A and 411A>T turned out to be monomorphic. Database comparisons of the NAT2 minor allele frequencies support that Romanians belong to Caucasians and Kyrgyz are in between Caucasians and East Asians. The distributions of predicted haplotypes differed significantly between the two ethnicities where the Kyrgyz showed a higher genetic diversity. The haplotype without mutations was more common in Kyrgyz (40.1% in Kyrgyz, 29.3% in Romanians). Accordingly, the imputed slow acetylator phenotype was less prevalent in Kyrgyz (35.2% versus 51.4% in Romanians). We found pronounced ethnic differences in NAT2 genotypes with yet unknown effect on the health risks for environmental or occupational exposures in minority populations.     

Gehörschäden durch Silvester-Feuerwerkskörper Befragung zur Inzidenz von Knall- und Explosionstraumata in der Bundesrepublik Deutschland zur Jahreswende 1998/99

In der Ausgabe 4/99 der HNO wurde in einer ausführlichen übersichtsarbeit die Gef?hrdung für das Geh?r durch Freizeitl?rm dargestellt [8]. Die Autoren hoben im besonderen die wachsende Zahl irreversibler Innenohrsch?den bei Kindern, Jugendlichen und jungen Erwachsenen hervor. In der Stellungnahme der Bundes?rztekammer werden mit dem Umweltbundesamt abgestimmte Pegelbegrenzungen für Diskotheken, tragbare Musikwiedergabeger?te sowie l?rmgebende Spielzeuge konkret vorgechlagen, so da? der Gesetzgeber eine klare Handhabe hat [6,7]. Feuerwerksk?rper spielen neben lauten Kinderspielzeugen, Musik bei Besuchen von Diskotheken oder Gro?veranstaltungen, tragbaren Musikabspielger?ten und Schie?l?rm eine urs?chliche Rolle für die im Freizeitbereich entstandene, l?rmbedingte Innenohrschwerh?rigkeit. Um das Ausma? der Geh?rsch?den durch Feuerwerksk?rper abzusch?tzen, wurde eine retrospektive Befragung bundesdeutscher HNO-Kliniken und HNO-Abteilungen zu Knall- und Explosionstraumata in der Silvesternacht 1998/99 durchgeführt. Die vorliegenden Ergebnisse machen die Aktualit?t der Problematik für die Pr?ventivmedizin und den weiteren Handlungsbedarf auch auf diesem Gebiet des Freizeitl?rms deutlich.     

Analysis of mdm2 and p53 Gene Alterations in Glioblastomas and its Correlation with Clinical Factors

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.