On the Interpolation of Data with Normally Distributed Uncertainty for Visualization.

In many fields of science or engineering, we are confronted with uncertain data. For that reason, the visualization of uncertainty received a lot of attention, especially in recent years. In the majority of cases, Gaussian distributions are used to describe uncertain behavior, because they are able to model many phenomena encountered in science. Therefore, in most applications uncertain data is (or is assumed to be) Gaussian distributed. If such uncertain data is given on fixed positions, the question of interpolation arises for many visualization approaches. In this paper, we analyze the effects of the usual linear interpolation schemes for visualization of Gaussian distributed data. In addition, we demonstrate that methods known in geostatistics and machine learning have favorable properties for visualization purposes in this case.

Wastewater treatment with submerged fixed bed biofilm reactor systems--design rules, operating experiences and ongoing developments.

Wastewater treatment systems using bio-films that grow attached to a support media are an alternative to the widely used suspended growth activated sludge process. Different fixed growth biofilm reactors are commercially used for the treatment of municipal as well as industrial wastewater. In this paper a fairly new fixed growth biofilm system, the submerged fixed bed biofilm reactor (SFBBR), is discussed. SFBBRs are based on aerated submerged fixed open structured plastic media for the support of the biofilm. They are generally operated without sludge recirculation in order to avoid clogging of the support media and problems with the control of the biofilm. Reactor and process design considerations for these reactors are reviewed. Measures to ensure the development and maintenance of an active biofilm are examined. SFBBRs have been applied successfully to small wastewater treatment plants where complete nitrification but no high degree of denitrification is necessary. For the pre-treatment of industrial wastewater the use of SFBBRs is advantageous, especially in cases of wastewater with high organic loading or high content of compounds with low biodegradability. Performance data from exemplary commercial plants are given. Ongoing research and development efforts aim at achieving a high simultaneous total nitrogen (TN) removal of aerated SFBBRs and at improving the efficiency of TN removal in anoxic SFBBRs.

Effect of temperature and salinity on the wastewater treatment performance of aerobic submerged fixed bed biofilm reactors.

The influence of temperature (5-35 C) and salinity (up to 20 g/l NaCl) on the wastewater purification process in completely mixed and aerated submerged fixed bed biofilm reactors (SFBBRs) was studied. C- and N-conversion in SFBBRs designed according to the DWA (German Association for Water, Wastewater and Waste) rules for carbon removal was investigated for several months on synthetic wastewater. The DOC degradation rate was even at, according to the DWA, high DOC/BOD loading rates not much affected by temperatures between 5-35 degrees C and salt contents up to 20 g/L NaCl. At these high DOC loadings an appreciable ammonium conversion could also be observed. The ammonium conversion proved to be sensitive to temperature and salinity. At 5 degrees C the ammonium removal rate decreased by a factor of five compared to 25-35 degrees C. Under many operation conditions investigated more than 50% of the converted ammonium was transformed into gaseous nitrogen. The addition of 20 g/L NaCl caused a strong inhibition of the ammonium removal rate over the whole temperature range investigated.

Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families.

Variance components models were used to analyze total IgE levels in families ascertained though the Collaborative Study of the Genetics of Asthma (CSGA) using a genome-wide array of polymorphic markers. While IgE levels are known to be associated with clinical asthma and recognized to be under strong genetic control (here the heritability was estimated at 44-60% in the three racial groups), specific genes influencing this trait are still largely unknown. Multipoint analysis of 323 markers yielded little indication of specific regions containing a trait locus controlling total serum IgE levels (adjusted for age and gender). Although a number of regions showed LOD statistics above 1.5 in Caucasian families (chromosome 4) and in African-American families (chromosomes 2 and 4), none yielded consistent evidence in all three racial groups. Analysis of total IgE adjusted for gender, age and Allergy Index (a quantitative score of skin test sensitivity to 14 common aeroallergens) was conducted on these data. In this analysis, a much stronger signal for a trait locus controlling adjusted log[total IgE] was seen on the telomeric end of chromosome 18, but only in Caucasian families. This region accounted for most of the genetic variation in log[total IgE], and may represent a quantitative trait locus for IgE levels independent of atopic response. Oligogenic analysis accounting simultaneously for the contribution of this locus on chromosome 18 and other chromosomal regions showing some evidence of linkage in these Caucasian families (on chromosomes 2, 4 and 20) failed to yield significant evidence for interaction.

Pathophysiology of severe asthma.

Although asthma affects nearly 8% of the adult population, most of these patients have mild-to-moderate disease that can be controlled with appropriate treatment. It is estimated, however, that 5% to 10% of patients with asthma have severe disease that is unresponsive to typical therapeutics, including corticosteroids. Because patients with severe asthma are disproportionately affected by their disease, in terms of both impaired lifestyle and health care costs, the National Heart, Lung, and Blood Institute sponsored a workshop on the pathogenesis of severe asthma. The goals of this workshop were to begin to define the characteristics of severe asthma. In these discussions, it was clear that many characteristics need to be considered in defining this phenotype of asthma, including symptoms, intensity of therapy (including administration of systemic corticosteroids), and impairment of lung function. Also discussed were potential mechanisms of severe asthma including the role of allergic diseases, which may play less of a role in severe asthma than in mild-to-moderate disease, and infections. A major limitation to control of severe asthma is the recalcitrant response of these patients to usual therapy including systemic corticosteroids; the potential of other therapies was reviewed. From these discussions, recommendations were made for future research needs to gain insights into a difficult therapeutic and possibly novel mechanistic area of asthma.

Epidural sufentanil during paediatric cardiac surgery: effects on metabolic response and postoperative outcome.

The metabolic and neuroendocrine effects of caudal epidural analgesia were studied during paediatric cardiac surgery. Combined epidural and general anaesthesia (EPI group; n=12) was compared with deep opioid anaesthesia (DOA group; n=12). During anaesthesia and surgery, haemodynamic stability was similar in the two groups. There was no significant difference between groups concerning the metabolic response to surgery but circulating catecholamines were significantly lower in the EPI group during and after surgery. Perioperative release of IL-6 was higher in the EPI group possibly reflecting a longer aortic clamp time. Incidence of postoperative life-threatening dysrhythmias was very low in the two groups. No significant reduction of postoperative mechanical ventilation, intensive care unit or hospital stays was reported with epidural analgesia. The incidence of postoperative infections was higher than expected in the two groups because of the poor properative clinical status of most of the children included in the study.

Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial.

Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopathology. Concomitantly, serum concentrations of clozapine and metabolites were measured during monotherapy and after addition of fluvoxamine. In all patients, the serum concentrations of clozapine and metabolites were markedly increased (average: 2-3 fold, up to 5 fold for clozapine) after addition of fluvoxamine. Side effects remained almost unchanged in frequency and severity in spite of the pharmacokinetic interactions. ECG or laboratory parameters and orthostatic tests were similar under monotherapy and comedication. Minimal increases of EEG abnormalities were observed, but they were not associated with clinical impairment. Epileptic activities were always absent. The psychopathology improved which continued after start of the comedication. Though the addition of fluvoxamine to clozapine medication was well tolerated and critical side effects were absent, the combined treatment should be controlled by drug monitoring, as serum concentrations of clozapine increased to unpredictably high levels. Further studies have to find out if the combined treatment could be advantageous to clozapine monotherapy.

Occupancy of striatal D(2)-like dopamine receptors after treatment with the sigma ligand EMD 57445, a putative atypical antipsychotic.

RATIONALE: EMD 57445 (panamesine) is a high affinity sigma ligand with the profile of an atypical antipsychotic in animal studies. It has been reported recently to have antipsychotic activity in schizophrenia. However, its metabolite, EMD 59983, binds also to D(2) and D(3) dopamine (DA) receptors. OBJECTIVES: The aim of this study was to test, using single photon emission computed tomography (SPECT) and [(123)I]iodobenzamide (IBZM) as the radiotracer, whether EMD 59983 would pass the blood-brain barrier and to what extent it would contribute to the effects of EMD 57445 in schizophrenia. METHODS: Two IBZM SPECT-scans were performed in five neuroleptic-free schizophrenic patients (DSM IV), one before and one after treatment with 60 mg panamesine daily for a treatment duration of 12-26 days. RESULTS: A high occupancy of striatal D(2)-like DA receptors similar to that induced by typical neuroleptics was observed in all patients treated with EMD 57445. CONCLUSIONS: Our results suggest that a possible antipsychotic activity of EMD 57445 in schizophrenia is not necessarily attributable to its affinity for sigma receptors, but could be simply due to the potent antidopaminergic effects of EMD 59983, its main metabolite.

Randomised placebo-controlled trial of moclobemide, cognitive-behavioural therapy and their combination in panic disorder with agoraphobia.

BACKGROUND: In the treatment of panic disorder with agoraphobia, the efficacy of pharmacological, psychological and combined treatments has been established. Unanswered questions concern the relative efficacy of such treatments. AIMS: To demonstrate that moclobemide and cognitive-behavioural therapy (CBT) are effective singly and more effective in combination. METHOD: Fifty-five patients were randomly assigned to an eight-week treatment of: moclobemide plus CBT; moclobemide plus clinical management ('psychological placebo'); placebo plus CBT; or placebo plus clinical management. RESULTS: Comparisons between treatments revealed strong effects for CBT. Moclobemide with clinical management was not superior to placebo. The combination of moclobemide with CBT did not yield significantly better short-term results than CBI with placebo. The CBT results remained stable during a six-month follow-up, although a substantial proportion of patients treated with placebo plus CBT needed additional treatment. CONCLUSIONS: CBT was highly effective in the treatment of panic disorder with agoraphobia and reduced agoraphobia to levels that were comparable to those of non-clinical controls.

Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides.

The expression of the Duffy Antigen/Receptor for Chemokines (DARC) on red blood cells (RBC) has been commonly determined using hemagglutination tests. Because the vast majority of African individuals are Duffy-negative, screening for DARC expression on RBC is a valuable tool to assess Caucasian admixture in populations of African descent. Furthermore, blood group antigens have been frequently tested as potential risk factors for complex diseases. We established a dot-blotting protocol using sequence-specific oligonucleotides (SSOs) for the DARC-46T ("Duffy-positive") and -46C ("Duffy-negative") alleles. With this method, but not with serological methods, Duffy-positive individuals can be further characterized as homozygous or heterozygous for the dominant Duffy-positive allele, allowing more precise estimation of allele frequencies and admixture in heterogeneous populations. In unrelated African American (n = 235), Afro-Caribbean (n = 90) and Colombian (n = 93) subjects, the frequency of the -46T allele was 21.7%, 12.2% and 74.7%, respectively. The percentage of Duffy-positive individuals (homozygous or heterozygous for the -46T allele) in each population was in accordance with published frequencies. As expected, the -46C allele was not detected in 20 Caucasian subjects. This sensitive and specific method allows for the rapid and inexpensive screening of large samples for Duffy genotypes using small quantities of genomic DNA.

Electrophysiological evidence for an inverse benzodiazepine receptor agonist in panic disorder.

Inverse agonists of the GABA(A) receptor clearly decrease the amplitudes of the spontaneous EEG in the beta-frequency range. Therefore, we tested the hypothesis that panic patients exhibit a reduction of the EEG's spectral power in the beta-frequency band. Ten unmedicated patients with panic disorder and agoraphobia according to DSM-III-R criteria and 10 matched controls were investigated under baseline conditions, after hyperventilation and 30 min after hyperventilation. EEG recordings from the position Pz and Cz were performed under eyes closed conditions. At baseline conditions the patients suffering from panic disorder depicted a reduced beta-power reaching statistically significance for lead position Pz. Immediately after hyperventilation for both channels we observed a decreased beta-power. After hyperventilation we observed the same situation as under baseline conditions. Taken together, our results point to the view that in panic disorder an endogenous inverse agonist of the GABA(A)-benzodiazepine receptor could be hypothesized.

Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial.

Clozapine is a drug with many side effects, some of them with potentially hazardous outcome (e.g. seizures, agranulocytosis), if not carefully monitored. It has been shown that the metabolism of clozapine may be affected by concomitant treatment with selective serotonin reuptake inhibitors (SSRIs), while there have been reports of improved efficacy on negative symptomatology of clozapine in combination with SSRIs. Therefore, this prospective open clinical trial was performed to investigate the safety and tolerability of the coadministration of clozapine and paroxetine under control of serum concentrations of clozapine and its metabolites and the effect of this combination treatment on psychopathological outcome was evaluated. A total of 14 patients suffering from schizophrenia or schizodepressive disorder with predominant negative symptomatology were included. The duration of the study was at least 6 weeks for each patient. Initial treatment was a monotherapy with clozapine at a daily dose of 2.5 mg/kg weight. After two measurements of serum concentrations of clozapine and metabolites during steady state conditions, an add-on therapy with 20 mg paroxetine was initiated. No concomitant medication was allowed. The main finding of our prospective study was that addition of paroxetine to a monotherapy with clozapine was a well tolerated medication that did not give rise to new clinically relevant side effects. After addition of paroxetine the serum concentrations of clozapine and its major metabolites remained virtually constant. The results of the psychopathological measurements indicated a further clinical improvement, although the small open study could not test for efficacy.

[123I]IBZM SPECT in patients treated with typical and atypical neuroleptics: relationship to drug plasma levels and extrapyramidal side effects.

[123I]Iodobenzamide (IBZM) is an iodine-labeled dopamine receptor ligand and can be used to visualize brain D2 receptors in humans with single photon emission computerized tomography (SPECT). The ratio of striatal IBZM uptake to uptake in frontal cortex (ST/FC ratio) represents a semiquantitative measure of D2 receptor binding in the striatum. Our study sample included six patients treated with haloperidol (3.0-8.0 mg/day orally; one patient with an average of 0.9 mg/day intramuscularly), five patients with benperidol (9.0-15.0 mg/day orally) and nine patients treated with clozapine (200.0-600.0 mg/day orally). Typical neuroleptics (TNs) and atypical neuroleptics (ANs) were significantly different in their ST/FC ratios. The ST/FC ratios indicated that patients treated with benperidol exhibited the lowest ST/FC ratios, with increasingly higher ratios in patients on haloperidol or clozapine. We found a curvilinear relationship between the ST/FC ratios and the dose/kg body wt. of TNs and ANs on the basis of a dose-normalization according to Ki-values of the neuroleptic at D2 receptors and a weaker, but also curvilinear relationship between ST/FC ratios and normalized dosages according to clinically defined chlorpromazine equivalents. The specific uptake of IBZM did not correlate with the plasma levels of the TN haloperidol at the present dose range (0-12.4 ng/ml). For clozapine, a meaningful negative correlation between plasma levels and ST/FC ratio could be established. There was a negative continuous correlation between uptake of IBZM and extrapyramidal side effects, which is different from the threshold-based relationship between extrapyramidal side effects and IBZM uptake reported previously.

Proton magnetic resonance spectroscopy in dementia of Alzheimer type.

Reduced N-acetyl aspartate (NAA) and increased myo-inositol (MI) levels have been reported in patients with dementia of Alzheimer type (DAT) in comparison with controls. We wished to assess the validity of these findings and to evaluate possible correlations of metabolite proportions with cognitive dysfunction in DAT. Twelve patients with DAT and 10 healthy age-matched controls were included. The severity of dementia was assessed using different scales including the Mini-Mental State Examination. MRS was performed with a conventional 1.5 Tesla scanner in a single voxel in the centrum semi-ovale (TE = 30 ms or TE = 136 ms; TR = 1500 ms). The evaluation of MRS results was limited by low interrater, intermeasurement (different echo times) and test-retest reliabilities, by a high interindividual variance and by the failure to measure absolute metabolite concentrations. These problems in mind, it was remarkable that previously reported reductions of NAA levels in patients with DAT could be reproduced in the present sample. The proportion of NAA was diminished in demented subjects in comparison with controls (37% vs 44.90%, short TE). A non-significant trend towards minor reductions of creatine, choline and MI proportions in these subjects might indicate that proportions of other metabolites necessarily increase when NAA is reduced. Cognitive dysfunction of demented subjects was significantly correlated with reductions of NAA, but not with increases of MI. Due to the present technical and methodological problems and to the non-specificity of findings, proton MRS cannot be applied to support the diagnosis of DAT in a clinical setting.

[Value of computerized tomography and magnetic resonance tomography in psychiatric diagnosis]. / Stellenwert von Computertomographie und Magnetresonanztomographie in der psychiatrischen Diagnostik.

This paper evaluates the role of computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of psychiatric disorders according to the "International Classification of Diseases" (ICD-10). Indications for CT/MRI can be derived from ICD-10 for the identification or exclusion of defined cerebral lesions resp. for the etiology in organic disorders. Due to the lack of specific morphological findings, CT/MRI do not contribute to the classification of all other diagnoses. CT/ MRI can only exclude causal organic factors. However, ICD-10 provides only few guidelines for ruling out cerebral pathology (e.g. tumors in bulimic anorexia). Therefore, recommendations for routine CT/MRI-investigations for the exclusion of organic disorders are required and might be developed by the quality assurance. Application of CT or MRI: CT plays an important role in diagnostic imaging in routine as well as in emergency situations (haemorraghe, hamatoma, infaction, head injury, tumour, vascular malformation). MRI on the other hand, is more sensitive in the diagnosis of inflammatory diseases, skull base lesions, degenerative changes of the white matter and in the imaging of hydrocephalus and epilepsy.

Expression of alpha subunit genes of nicotinic acetylcholine receptors in human lymphocytes.

Using immunohistochemistry and in situ hybridisation, we have studied whether alpha-subunits of nicotinic acetylcholine receptors (nAChRs) are expressed in human lymphocytes. Cells were isolated by differential low speed gradient centrifugation from heparinised venous blood of 10 healthy volunteers. Receptor sites were visualised using the monoclonal antibody WF6 which specifically recognises alpha-isoforms from several species including man. For visualisation of transcripts, digoxigenin-labelled cRNA probes for alpha 4- and alpha 3-subunits were used. Immunostaining revealed specific binding of WF6 to isolated human lymphoid cells. The antibody was bound to most cells and concentrated preferentially in the perinuclear/surface region. The immunoreactivity resembled that observed after application of an antibody recognising CD4 surface proteins which was conducted for comparison. In situ-hybridisation revealed that the alpha 4-subunit genes of nAChRs was expressed in lymphocytes of all probands. The alpha 3-subunit was found, with lower intensity than alpha 4-transcripts, in eight of the 10 individuals. Control incubations with corresponding sense cRNAs were negative. It is concluded that human lymphocytes are able to express alpha-subunit genes of nAChRs.

Prolactin plasma levels and D2-dopamine receptor occupancy measured with IBZM-SPECT.

By the application of 123([123I]IBZM), an iodine-labelled dopamine D2-receptor antagonist, brain D2 receptors in humans can be visualized with single photon emission computed tomography (SPECT). The ratio of IBZM binding to striatal regions versus binding to frontal cortex (ST/FC ratio) provided a semiquantitative measurement of D2 receptor binding in the striatum. This study investigated the relationship between receptor occupancy and plasma prolactin levels in 12 male patients treated with haloperidol, benperidol or clozapine. Prolactin levels were positively correlated with D2 receptor occupancy, reflecting at least in part a comparable dopamine receptor antagonism in different dopaminergic pathways.