CCND1 and ZNF217 gene amplification is equally frequent in BRCA1 and BRCA2 associated and non-BRCA breast cancer.

Breast cancer associated with BRCA1 and BRCA2 gene mutations differs from non-BRCA tumors in several respects. We determined whether there was any difference in CCND1 (11q13) and ZNF217 (20q13) gene amplification with respect to BRCA status. Of 40 breast cancer samples examined, 15 and 9 were from BRCA1 and BRCA2 mutation carriers, respectively, and 16 from patients without mutation. Fluorescence in situ hybridization showed that eight tumors exhibited CCND1 amplification (20%; 3 BRCA1, 3 BRCA2, 2 non-BRCA). ZNF217 amplification was observed in three of 38 cases (8%; 2 BRCA1, 1 non-BRCA). There was no significant difference in CCND1 and ZNF217 amplification between BRCA1, BRCA2 and non-BRCA tumors. CCND1 amplification was associated with decreased disease-free (P = 0.045) and overall survival (P = 0.015). BRCA1 tumors with CCND1 amplification were estrogen receptor negative, in contrast to CCND1 amplified BRCA2 and non-BRCA tumors, suggesting that concurrent CCND1 amplification and estrogen and progesterone receptor negativity may predict germline BRCA1 gene mutation. All ZNF217 amplified tumors were of the medullary histological type (P = 0.002). There was no statistical correlation between CCND1 and ZNF217 amplification and estrogen receptor, progesterone receptor, and ERBB2 expression and TNM classification. CCND1 amplification did not correlate with EGFR expression.

Severe adverse drug reactions in psychiatric inpatients treated with neuroleptics.

Numerous studies compare side effects or adverse drug reactions (ADRs) of the various typical and newer atypical neuroleptics in patients with schizophrenia. However, these studies, as controlled randomized trials, represent an artificial setting of drug administration and do not easily relate to the "real-life" setting of psychiatric treatment. In contrast, the AMSP drug safety program allows the monitoring of ADRs of all types of psychopharmacological agents in the naturalistic setting of routine clinical practice. In the present study, the data on neuroleptics acquired in the AMSP program from 1993 to 2000 are analyzed. In this period, 86,439 patients treated with at least one neuroleptic agent were monitored. In 1.1 % of the patients severe ADRs occurred. In contrast to the results from controlled trials, atypical neuroleptics caused more severe ADRs than did typical neuroleptics. This result was mainly caused by the high number of severe ADRs in patients treated with clozapine and concerned delirium and non-EPS neurological, gastrointestinal, hepatic, dermatological, hematological, and endocrinological ADRs. Atypical neuroleptics were found to be superior in EPS and urological ADRs. Excluding the data on clozapine, we found typical and atypical neuroleptics to be similar in the occurrence of severe ADRs, although the profiles differ between these two groups as well as between the single substances. Our findings provide valuable information on the type and frequency of ADRs in psychiatric practice, thus enabling differential indication of neuroleptics based not only on the efficacy and tolerability data of controlled trials but also on their differential ADR profile occurring in the "real-life" setting of routine clinical treatment.

[Subjective experience of a computer-assisted cognitive training by patients with schizophrenia]. / Subjektives Erleben eines computergestützten kognitiven Trainings durch Patienten mit Schizophrenien.

Cognitive training is an important aim of treatment for patients with schizophrenia. However, computer-based cognitive training is still not widely used, and there are reservations concerning the use of computers in psychiatric treatment. In a multicentre study, 64 patients with schizophrenia were investigated before and after completing a 5-week course of computer-based cognitive training using the program Cogpack. In addition to self-rating of computer anxiety (CARS) and subjective well-being (SWN), patients underwent semistructured interviews evaluating attitudes towards the training. The training was rated as highly acceptable by patients and experienced as very effective. Patients' expectations of possible training effects were largely met. The training ranked high in patients' judgement compared with other treatments received. Besides improvement in cognitive function (primary effect), patients enjoyed the training and reported increased self-esteem and progress in using computers (secondary effects). Computer anxiety scores at onset of treatment did not exceed normal values. After completion of the training, these scores were significantly reduced and subjective well-being significantly increased.

Dorsolateral prefrontal cortex activation during automatic auditory duration-mismatch processing in humans: a positron emission tomography study.

This study aimed to identify the neural networks underlying automatic and active auditory deviant detection in six healthy subjects using positron emission tomography. Eight alternating blocks of standard and standard plus duration-deviant tones were presented while subjects performed a visual discrimination task. In an additional four blocks, the subjects then performed an auditory discrimination task on the deviant tones. Actively attending the deviant tones increased regional cerebral blood flow (rCBF) in the superior temporal and inferior frontal gyrus as well as in the superior and medio-frontal gyrus. When performing the visual task and presented with deviant tones, significant increase of rCBF was detected in the caudate nucleus, cerebellum, posterior cingulate, inferior frontal and pre-central gyrus thus indicating automatic extra-pyramidal processing of auditory duration deviants.

Attention-dependent allocation of auditory processing resources as measured by mismatch negativity.

Mismatch negativity (MMN) is a pre-attentive event-related potential measure of echoic memory. However, recent studies suggest attention-related modulation of MMN. This study investigates duration-elicited MMN in healthy subjects (n = 12) who were performing a visual discrimination task and, subsequently, an auditory discrimination task in a series of increasing task difficulty. MMN amplitude was found to be maximal at centro-frontal electrode sites without hemispheric differences. Comparison of both attend conditions (visual vs. auditory), revealed larger MMN amplitudes at Fz in the visual task without differences across task difficulty. However, significantly smaller MMN in the most demanding auditory condition supports the notion of limited processing capacity whose resources are modulated by attention in response to task requirements.

Development and topography of auditory event-related potentials (ERPs): mismatch and processing negativity in individuals 8-22 years of age.

How do event-related potentials (ERPs) reflecting auditory processing develop across adolescence? Such development was described for five ERP components in four groups of 11 healthy participants with mean ages of 10, 14, 17, and 21 years. Data from 19 sites during diffuse (passive) and focused (discrimination) attention in a three-tone oddball were analyzed to see how ERP loci varied with age for tone type, attention condition, and for four types of difference waves reflecting nontarget and target comparisons. Age interacted with site for most components. P1 loci sensitive to rare tones moved posteriorly and N1 loci lost their right bias in early puberty. The P2 loci did not move anterior to Cz until adulthood. N2 amplitude, sensitive to attention condition, developed a frontal focus by 17 years. Right-biased P3 loci moved to the midline with focused attention similarly in all age groups. Difference waves developed in three stages: In 10-year-old participants, early deflections (< 150 ms) were diffusely distributed; in midadolescent participants, the main frontal negative component (150-300 ms) became well formed and lost an earlier right bias; and for participants 17 years old and older, the late positive complex developed a right bias in target-derived waves. Latency decreases for early frontal components were marked in participants 10-14 years old and for later posterior components in participants 14-17 years old. Major developments appeared at the onset of adolescence in early stimulus selection processes and during adolescence in the differential use of this information (N2- and P3-like latencies).

Impaired attention-dependent augmentation of MMN in nonparanoid vs paranoid schizophrenic patients: a comparison with obsessive-compulsive disorder and healthy subjects.

Mismatch negativity (MMN), in the deviant-minus-standard event-related potential (ERP) difference-waveform, may represent a working memory trace of the tone difference. Most but not all studies find MMN reduced in schizophrenic patients. This report investigates if differences may be attributable to experimental condition (diffuse vs focused attention), component identification (N1-like vs N2-like), topographic distribution, and clinical condition (with/without paranoid-hallucinatory symptoms, PH/NP). Comparisons were made for 12 PH, 12 NP schizophrenic patients with 13 obsessive compulsive and 25 normal control subjects. Frontal MMN reduction in schizophrenics largely resulted from an absence of an increase in focused attention conditions as in comparison groups. But there was a marked temporal activity locus in NP patients. These features were not reflected in other components except for a visible but nonsignificant N1-like temporal locus in NP patients. Further, schizophrenic patients did not show an increase in late positivity with focused attention like the comparison groups. The results show that so-called automatic processing deficits (amount and locus of MMN) are best seen in situations requiring the activation of controlled attentional processes. It is suggested that impaired processing of irrelevant stimuli and reduced frontal MMN in NP patients may reflect reduced dopaminergic responsivity.

Auditory event-related potential (ERP) and difference-wave topography in schizophrenic patients with/without active hallucinations and delusions: a comparison with young obsessive-compulsive disorder (OCD) and healthy subjects.

Event-related potentials (ERPS) in schizophrenics have been reported to show a reduced P3 on the left and less frontal mismatch negativity (MMN). But the specificity of such findings to component, its locus, the type of eliciting event and patient group remains uncertain. Hence, we examined ERP topography for P3, N2 and 3 precursor peaks according to stimulus (3-tone oddball), attention condition (diffuse/focused) and four types of difference-waves. We contrasted 24 healthy and 13 OCD subjects with schizophrenic patients with high versus low ratings of active delusions and hallucinations (12 paranoid-hallucinatory, PH; 12 nonparanoid, NP). P3 peaks were delayed and reduced in NP and PH groups. Midline peaks were usual in focused attention and a right bias in diffuse attention. P3 responses to irrelevant standards remained lateral in NP and small in OCD patients. All showed a small left and anterior bias in the P3-like peak in difference-waves. Mismatch negativity waveform (MMN) peaks shifted to the right in OCD, to both sides in PH and posteriorly in NP patients. Frontal processing negativity was biased to the left (early) in NP and to the right (late) in PH groups. Early peak topography reflected some later changes (e.g. PH and NP groups; P1-like peak, right bias absent; N1-like peak depressed and widely distributed; NP group, P2-like peak smaller on the left). In OCD patients, peak latencies were topographically undifferentiated (P1, P2) or delayed (N2). The OCD group showed an unusual regional allocation of processing effort. Before 200 ms frontocentral activity was more widespread in Ph and NP groups. Lateralization of negativity in target- and nontarget-derived difference-waves may reflect differential disruption of the frontal-temporal dialogue in registering important vs unimportant features. NP patients, in particular, treated irrelevant stimuli anomalously.

Auditory event-related potentials (ERPs) and mismatch negativity (MMN) in healthy children and those with attention-deficit or tourette/tic symptoms.

The study compares 5 auditory event-related potential (ERP) components (P1 to P3) after 3 tones differing in pitch and rarity, and contrasts the mismatch negativity (MMN) between them in 12 children with attention-deficit hyperactivity disorder (ADHD; mean 10.2 years of age), 12 healthy controls pairwise matched for age (controls), and 10 with Chronic Tic or Tourette Syndrome (TS). Topographic recordings were derived from 19 scalp electrodes. Four major effects are reported. (a) Shorter latencies in ADHD patients were evident as early as 100 ms. (b) Both ADHD and TS groups showed very large P2 components where the maxima were shifted anteriorly. The differences in the later potentials were of a topographical nature. (c) Frontal MMN was non-significantly larger in the ADHD group but normalized data showed a left rather than a right frontal bias as in control subjects. Maxima for TS were usually posterior. (d) ADHD patients did not show the usual right-biased P3 asymmetry nor the frontal versus parietal P3 latency difference. From these results it is suggested that ADHD patients process perceptual information faster from an early stage (N1). Further, along with the TS group, ADHD patients showed an unusually marked inhibitory phase in processing (P2), interpreted as a reduction of the normal controls on further processing. Later indices of stimulus processing (N2-P3) showed a frontal impairment in TS and a right hemisphere impairment in ADHD patients. These are interpreted in terms of the difficulties in sustaining attention experienced by both ADHD and TS patients.

Mismatch negativity (MMN) is altered by directing attention.

MMN is a negative component resulting from the difference in event-related potential (ERP) waveforms elicited by a standard and a deviant stimulus. It is usually studied in the absence of attentional requirements. We compared this measure of perceptual comparison in a non-task situation (three tones presented) with that obtained in a task requiring focused attention and response to the third tone. MMN (comparison of standard and deviant irrelevant tones) increased with focused attention to the third (target) tone and frontal maxima shifted slightly posteriorly. The succeeding P3 in the difference waveform increased more posteriorly than frontally confirming continued differential processing of irrelevant stimuli under active conditions. This demonstrates that not only attending to stimuli, but the active processing of irrelevant stimuli (vs passive perception) involves small changes in the amount and distribution of neural activity.

The topography of event-related potentials in passive and active conditions of a 3-tone auditory oddball test.

Normalized event-related potential (ERP) data were analysed for topographical differences of ERP amplitude or latency in two conditions of a 3-tone oddball paradigm. The aim was to compare perception-related features relating to tone-type (passive non-task condition) with focussed attention-related features (active discrimination of target from non-target) in 5 ERP components from 23 young healthy subjects. The tones used were a common standard (70%, 0.8 KHz), a deviant standard (15%, 2 KHz) and a 1.4 KHz tone (15%, t) also used as the target (T). A site x tone interaction was obtained for P1 amplitude (augmenting with pitch anterior to posterior). The opposite tendency was seen for P2 to the right of midline maxima. No interaction was obtained for N1 amplitude. Condition became relevant for the N2-P3 complex. Frontal N2 amplitude increased after rare tones in the active condition. Posterior P3 peak size distinguished between tone (more widespread response to the common tone) and condition (more right-sided in the passive condition). The common tone elicited more widespread shift to the right than the rare tones. Latency was affected by condition from the P2 onwards and confirmed many of the amplitude interactions. This report extends and qualifies well-known main effects of tone and condition through main site effects to lateral sites. It supports claims of multiple sources of ERP components, except for N1 and P2. The contributions of these sources are influenced by tone-features (from P1) and the presence or absence of focussed attention (from the N2-P3 complex).

The topography of 4 subtraction ERP-waveforms derived from a 3-tone auditory oddball task in healthy young adults.

Five components were studied in 4 subtraction waveforms derived from ERPs obtained in passive and active conditions of a 3-tone oddball task (common = 70%, C, 0.8 KHz; deviant = 15%, D, 2 KHz; 1.4 KHz = 15%, t, also used as a target (T)). These waveforms reflect different stimulus-mismatch processes and thus their topography could be revealing of different brain regions mediating them. The following mismatches were studied: stimulus-mismatch (deviant--common, D/C, rarity and pitch confounded), pitch-mismatch (T--deviant, T/D, rarity not target features controlled), attention-mismatch (T-t), T/t, controlled for pitch and rarity to show the influence of target features). These are compared with Goodin's procedure [G-wv, (T--common (active))--(t--common (passive))]. There were main site effects in normalized data in all cases (not P2 and N2 latency). There were separate frontal and posterior contributions to P1, with the former emphasized where target comparisons were involved. Frontal N1 peaks, largest in D/C, spread posterior and to the right where target matching was involved. P2 posterior maxima were also less localized where target features were involved in the comparison. N2 topography was similar between waveforms but spread slightly more to each side in the T/t comparison. Onset was earlier in the D/C comparison. Parietal P3 peaks in waves based on target-ERPs showed a left temporal shift (vs D/C), though in T/D P3 was in fact maximal on the right. Thus an attentional effect is evident as early as 60 ms. Target features modify the anteroposterior distribution of positivity and negativity for the early components and in the lateralization of P3-like positivity. A comparison of waveforms by latency of potential shift (running t-test) vs peak identification (MANOVA) is illustrated and discussed. D/C and T/t (rather than T/D or G-wv) waveforms are recommended for distinguishing comparator mechanisms for stimulus- and task-relevant features.