No association of clock gene T3111C polymorphism and affective disorders.

CLOCK was hypothesised to be related to susceptibility of affective disorders. To test subsamples of affectively disordered patients, we examined age of onset (AoO), numbers of episodes and melancholic type of clinical manifestation. Using PCR and RFLP, we investigated in patients with unipolar depression and bipolar disorder (BP) whether the CLOCK T3111C SNP is associated with affective disorders (n=102) compared to healthy controls (n=103). No differences were found either in genotype or allele frequency distributions of T3111C polymorphism between patients compared to healthy controls (p>0.2). No deviations from Hardy-Weinberg Equilibrium (HWE) were detected either in patients, or healthy controls. Results suggest that there is no association between the T3111C SNP and affective disorders in general. Data of our sample replicate prior findings of Desan et al. [Am. J. Med. Genet. 12 (2000) 418]. Subsamples of patients with high numbers of affective episodes did show some deviations in genotypes (p=0.0585).

Study of family history in seasonal affective disorder.

OBJECTIVE: In our investigation we assessed the risk of morbidity for psychiatric disorders among the first-degree relatives of patients with seasonal affective disorders (SAD) and compared it with a control group of patients suffering from nonseasonal mood disorders (NSMD). METHODS: Over a period of 12 months (June 1994 to May 1995) we recruited patients consecutively admitted to our psychiatric university outpatient clinic in a prospective study. All patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, revised 4th edition. A total of 344 patients presented themselves with a diagnosis of affective disorder. Out of these, 36 were diagnosed as having SAD. From the same group of 344 patients, we selected a matched control group of 36 patients suffering from NSMD. The experimental and control groups were matched according to sex, age, severity of illness and number of siblings. RESULTS: There was no significant difference concerning the lifetime prevalences for psychiatric disorders among the fist-degree relatives in both groups (SAD = 16.5% and NSMD = 19%). CONCLUSION: It seems that there is no difference in familiarity for psychiatric disorders between SAD and NSMD.

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.

PTA versus Palmaz stent placement in femoropopliteal artery obstructions: a multicenter prospective randomized study.

PURPOSE: To evaluate if stent placement is superior to percutaneous transluminal angioplasty (PTA) in the treatment of chronic symptoms in short femoropopliteal arterial lesions. MATERIALS AND METHODS: One hundred fifty-four limbs in 141 patients who ranged in age from 39 to 87 years (mean age, 67 years) were randomized to PTA (n = 77) versus PTA followed by implantation of Palmaz stents (n = 77). Inclusion criteria were patients with intermittent claudication (n = 108, Society of Vascular Surgery/International Society of Cardiovascular Surgery [SVS-ISCVS] categories 1-3) or chronic critical limb ischemia (n = 46 with either ischemic rest pain [category 4] or minor tissue loss [category 5]), short stenosis or occlusion (lesion length < or = 5 cm), and at least one patent run-off vessel at angiography. Follow-up included clinical assessment, measurement of ankle/ brachial index (ABI), color duplex ultrasound, and/or angiography at 6 or 12 months. Angiographic follow-up between 12 and 36 months was available in 46 limbs (29.9%). RESULTS: In the PTA group, initial technical success was achieved in 65 of 77 limbs (84%) versus 76 of 77 (99%) limbs in the stent group (chi2 value = 0.009). Overall, major complications occurred in 3.9% (n = 6); n = 4 in the PTA group compared to n = 2 in the stent group. There was no difference between groups of treatment: hemodynamic/clinical success at 1 and 2 years in the PTA group was 72% and 65% versus 77% and 65% in the stent group (Gehan P value = .26). The cumulative 1- and 2-year angiographic primary patency rates were 63% and 53%, respectively, for both groups. The secondary 1- and 2-year angiographic patency rates were 86% and 74% in the PTA group versus 79% and 73% in the stent group (P = .5). CONCLUSION: After stent placement, the primary success rate was significantly higher than after PTA. However, 1-year angiographic and clinical/hemodynamic success was not improved.

Genome scan for susceptibility loci for schizophrenia.

OBJECTIVE: Schizophrenia is a relatively common, often chronic and debilitating mental illness. Evidence from various studies has clearly demonstrated that genetic factors contribute substantially to the etiology. The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHODS: A genome-wide map of 388 microsatellite DNA markers was genotyped in 5 schizophrenia families. Nonparametric linkage analysis (Genehunter) was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genome-wide level of statistical significance (p < 0.00002) or a p value suggestive of linkage (p < 0.007) for any marker; however, one p value suggested replicated linkage (p < 0.01) at chromosome 6p24 in region D6S309 (p = 0.0047). Furthermore, 11 markers resulted in p < 0.05 at chromosomes 6p, 6q, 10q, 12q and 14q. CONCLUSIONS: Despite the differences in diagnostic schemes, in markers used and methods of analyses between studies published so far, we think that our result supports the notion that there is possibly some consistent evidence for replicated linkage of a schizophrenia susceptibility locus around the region of D6S309 at chromosome 6p24.

Association studies of candidate genes in bipolar disorders.

The aim of the investigation was to test genes for predisposition to bipolar affective disorder. Therefore, we studied candidate genes in a sample of unrelated patients (n = 102) and healthy controls (n = 79) of Austrian origin, searching for a possible association between polymorphic DNA markers of 5 candidate genes (serotonin transporter, 5-HTT; serotonin 2a receptor, 5-HT2a; dopamine D2 receptor, DRD2; dopamine D3 receptor, DRD3; dopamine transporter, DAT1) and bipolar disorder. There was an association between allelic and genotypic frequencies of 5-HTT and affection status (p = 0.014 and p = 0.017, respectively). However, after correction for multiple comparisons (Bonferroni), these results did not remain significant. Nevertheless, the findings might suggest that alterations in the structure of 5-HTT are involved in the pathogenesis of bipolar disorder, which could have major implications in treatment. No association between 5-HT2a, DRD2, DRD3, DAT1 and bipolar disorder was found.

Association study of schizophrenia spectrum disorders and dopamine D3 receptor gene: is schizoaffective disorder special?

Alterations in dopamine neurotransmission have been hypothesized to play a role in the etiology of schizophrenia. We considered the dopamine D3 receptor gene on chromosome 3 as a candidate gene for an association analysis. We compared PCR-based genotype markers for healthy controls (n=120) and patients (n=95) with schizophrenia and schizophrenia spectrum disorders as diagnosed by consensus according to DSM-III-R. Our results possibly indicate an association of schizoaffective disorder with DRD3 homozygosity (P=0.056).

Stationary and integrated autoregressive neural network processes.

We consider autoregressive neural network (AR-NN) processes driven by additive noise and demonstrate that the characteristic roots of the shortcuts-the standard conditions from linear time-series analysis-determine the stochastic behavior of the overall AR-NN process. If all the characteristic roots are outside the unit circle, then the process is ergodic and stationary. If at least one characteristic root lies inside the unit circle, then the process is transient. AR-NN processes with characteristic roots lying on the unit circle exhibit either ergodic, random walk, or transient behavior. We also analyze the class of integrated AR-NN (ARI-NN) processes and show that a standardized ARI-NN process "converges" to a Wiener process. Finally, least-squares estimation (training) of the stationary models and testing for nonstationarity is discussed. The estimators are shown to be consistent, and expressions on the limiting distributions are given.

Non-association of dopamine D4 and D2 receptor genes with personality in healthy individuals.

Recently, different research groups reported conflicting results with regard to an association of dopamine 4 receptor (DRD4) genotypes and the personality dimension of novelty seeking (NS). High scores for NS seemed to be associated with long alleles of a DRD4 polymorphism. Furthermore, an association between personality traits and the dopamine 2 (DRD2) receptor gene was reported. NS and persistence (PS) high scores seemed to be associated with alleles of DRD2. We examined 109 (78 female and 31 male) normal healthy individuals using Cloninger's Temperament and Character Inventory (TCI) in order to replicate these findings. We genotyped a 48 base pair variable number of tandem repeats (from two to eight repeats) polymorphism in the third exon of DRD4 and a Cys311Ser polymorphism in exon 7 of DRD2. We tested alleles and genotypes of DRD4 (allele 7 absent or present; genotype 4,4 versus 4,7), and Ser/Cys and Cys/Cys genotypes of DRD2 for associations with TCI values. NS and the alleles and genotypes of DRD4 did not show any association. In associating the genotypes of DRD2 with TCI scales (NS, harm avoidance, reward dependence and PS), we also found no association. Recent findings associating NS with DRD4 could not be replicated. With regard to DRD2, we tested a different polymorphism as published recently and could not find an association of TCI scales with the gene. The present results therefore do not provide evidence that the DRD2 and DRD4 receptor genes contribute a common and relevant effect to personality traits.

Local PCA algorithms.

Within the last years various principal component analysis (PCA) algorithms have been proposed. In this paper we use a general framework to describe those PCA algorithms which are based on Hebbian learning. For an important subset of these algorithms, the local algorithms, we fully describe their equilibria, where all lateral connections are set to zero and their local stability. We show how the parameters in the PCA algorithms have to be chosen in order to get an algorithm which converges to a stable equilibrium which provides principal component extraction.

Possible association between childhood absence epilepsy and the gene encoding GABRB3.

BACKGROUND: Childhood Absence Epilepsy (CAE) is considered to have a predominantly, perhaps exclusively, genetic background. To date, genes responsible for susceptibility to CAE have not been identified. The object of the present study was to test association between CAE and the genes encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits alpha 5 (GABRA5) and beta 3 (GABRB3) located on the long arm of chromosome 15 (15q11-q13). METHODS: A family-based candidate gene approach was applied: 50 Austrian nuclear families ascertained for the presence of an affected child were investigated. GABRA5 and GABRB3 subunit genes were genotyped using DNA gained from peripheral blood samples by Polymerase Chain Reactions (PCR). Genetic association was tested using a Monte Carlo Version of the multi-allele Transmission-Disequilibrium Test (TDT). RESULTS: The TDT displayed significant overall association with GABRB3 (p = .0118). CONCLUSIONS: The present data suggest that the tested polymorphism may be either directly involved in the etiology of CAE or in linkage disequilibrium with disease-predisposing sites.

Efficacy of fluoxetine in Austrian patients with obsessive-compulsive disorder.

In an 8-week double-blind placebo-controlled trial we studied the efficacy of fluoxetine (FLX) in 53 Austrian patients with obsessive compulsive disorder (OCD) diagnosed according to DSM-III-R. The dosage of FLX was fixed at either 20, 40, or 60 mg per day. Response was prospectively defined as an at least 25% reduction on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and an improvement on Clinical Global Impression (CGI) rating to at least "much improved" at the endpoint. Patients treated with at least 40 mg FLX per day showed significantly higher response rates than did those receiving either placebo or FLX 20 mg/day. Compulsions were more reduced than obsessions and we also observed a strong placebo effect which is largely attributable to an improvement in the Y-BOCS compulsion subscore.

Behavioral effects of tryptophan depletion in seasonal affective disorder associated with the serotonin transporter gene?

There is some evidence that the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) may be involved in the pathogenesis of seasonal affective disorder (SAD). Short-term tryptophan (TRP) depletion was carried out in 18 drug-free remitted patients who met DSM-IV criteria for SAD. Behavioral effects were measured with the Hamilton Depression Rating Scale (HDRS) both 24 h before and 24 h after TRP depletion. Some of the patients showed behavioral responses such as lowered mood, feelings of guilt, loss of interest, agitation, loss of energy, fatigue, social withdrawal, increased appetite, and carbohydrate craving. It was the aim of our study to investigate whether the genotypes of the serotonin transporter gene were associated with symptoms of transient depressive relapse after TRP depletion. In addition, we matched the SAD patients with healthy control subjects to see if alleles and genotypes of the serotonin transporter gene were associated with SAD. High molecular weight DNA was isolated from peripheral blood leukocytes using standard methods. For the 5-HTT receptor gene, a 17-bp repetitive element of intron 2 was genotyped (variable number tandem repeat, VNTR). Alterations in HDRS scores after TRP depletion showed no significant association with alleles or genotypes of the 5-HTT gene, although heterozygotes showed a trend toward increased HDRS scores. The serotonin transporter is known to play a critical role in the termination of serotonergic neurotransmission by sodium-dependent uptake of 5-HT into the presynaptic neuron. The present study in a small group of SAD patients was unable to demonstrate that the 5-HTT gene plays a role in the pathogenesis of SAD or in short-term depressive relapse after TRP depletion.

The Tridimensional Personality Questionnaire as a predictor of relapse in detoxified alcohol dependents. The European Fluvoxamine in Alcoholism Study Group.

Personality traits have been found as strong predictors for treatment response in different psychiatric disorders. We administered the Tridimensional Personality Questionnaire, which measures the three personality dimensions: novelty seeking, harm avoidance (HA), and reward dependence, as introduced by Cloninger in a multicenter study (11 centers in the United Kingdom, Eire, Switzerland, and Austria) with detoxified alcohol-dependent patients (n = 521). The objective of this study was to evaluate a possible predictive value of these three dimensions on relapse over 1 -year follow up. A logistic regression analysis showed that novelty seeking is a strong predictor for relapse in detoxified male alcoholics (p = 0.0007; p values adjusted for treatment), but not in females. In both sexes, HA and reward dependence were of no predictive value. However, we found a trend for significance of HA for predicting "early" relapse (4 weeks) in females (p = 0.074). Our results show that Tridimensional Personality Questionnaire personality traits have direct clinical applications for prediction of relapse in detoxified alcohol dependents and indicate the necessity of additional therapeutic treatment in risk groups.

Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakastani patients.

The dopamine D3 receptor (DRD3) appears to play an important role in the mediation of antipsychotic drug action. Genetic association of treatment response to the atypical antipsychotic drug clozapine with the DRD3 polymorphism Ser9Gly was investigated in a sample of 32 schizophrenic patients. We found association of treatment response with allele Gly-9 (P=0.0058) and with genotypes consisting of Gly-9 (P=0.033) by this pharmacogenetic approach. A combined analysis with two previous studies (Shaikh et al., Hum. Genet. 97 (1996) 714-719; Malhotra et al., Mol. Psychiatry 3 (1998) 72-75) further substantiates these results (P=0.0041).

Optimal linear compression under unreliable representation and robust PCA neural models.

In a typical linear data compression system the representation variables resulting from the coding operation are assumed totally reliable and therefore the solution in the mean-squared-error sense is an orthogonal projector to the so-called principal component subspace. When the representation variables are contaminated by additive noise which is uncorrelated with the signal, the problem is called noisy principal component analysis (NPCA) and the optimal MSE solution is not a trivial extension of PCA. We first show that the problem is not well defined unless we impose explicit or implicit constraints on either the coding or the decoding operator. Second, orthogonality is not a property of the optimal solution under most constraints. Third, the signal components may or may not be reconstructed depending on the noise level. As the noise power increases, we observe rank reduction in the optimal solution under most reasonable constraints. In these cases it appears that it is preferable to omit the smaller signal components rather than attempting to reconstruct them. This phenomenon has similarities with classical information theoretical results, notably the water-filling analogy, found in parallel additive Gaussian noise channels. Finally, we show that standard Hebbian-type PCA learning algorithms are not optimally robust to noise, and propose a new Hebbian-type learning algorithm which is optimally robust in the NPCA sense.

Cross-validation with active pattern selection for neural-network classifiers.

We propose a new approach for leave-one-out cross-validation of neural-network classifiers called "cross-validation with active pattern selection" (CV/APS). In CV/APS, the contribution of the training patterns to network learning is estimated and this information is used for active selection of CV patterns. On the tested examples, the computational cost of CV can be drastically reduced with only small or no errors.

Biperiden and haloperidol plasma levels and extrapyramidal side effects in schizophrenic patients.

Anticholinergic drugs such as biperiden are used for the treatment of extrapyramidal side effects (EPS) induced by neuroleptics such as haloperidol. The effects of biperiden and haloperidol plasma levels on EPS were studied in 29 chronically ill schizophrenics. The results show relationships between biperiden dose and biperiden plasma levels (BPL), and between BPL and haloperidol plasma levels (HPL). Neither BPL nor HPL seem to influence EPS.

Adaptive combination of PCA and VQ networks.

In this paper we consider the principal component analysis (PCA) and vector quantization (VQ) neural networks for image compression. We present a method where the PCA and VQ steps are adaptively combined. A learning algorithm for this combined network is derived. We demonstrate that this approach can improve the results of the successive application of the individually optimal methods.