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H Sauer

Publications and source records attributed to H Sauer.

At least 109 records · Page 6Linked to original sources
PubMed1998

D2 dopamine receptor up-regulation, treatment response, neurological soft signs, and extrapyramidal side effects in schizophrenia: a follow-up study with 123I-iodobenzamide single photon emission computed tomography in the drug-naive state and after neuroleptic treatment.

BACKGROUND: Animal and postmortem studies indicate that neuroleptic therapy may induce D2 dopamine receptor up-regulation in the basal ganglia. METHODS: To address this phenomenon in a clinical study, we investigated the D2 dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and 3 days after completion of a standardized neuroleptic therapy (benperidol 12-16 mg/day, for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 hours after intravenous injection of 185 MBq 123I-iodobenzamide. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favorable versus a poor treatment response. RESULTS: Neuroleptic treatment led to decreased BG/FC ratios in patients with a favorable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = .06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects but not with neurological soft signs. CONCLUSIONS: Our findings suggest that neuroleptic therapy may induce D2 dopamine receptor up-regulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.

Adult↗
PubMed1998

Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids.

Growing multicellular prostate tumor spheroids develop quiescent cell subpopulations in central regions with features of intrinsic multicell-mediated drug resistance. Doxorubicin (dox) uptake was significantly reduced in large spheroids (diameter 400+/-70 microm), which consist predominantly of quiescent cells, as compared to small spheroids (diameter 100+/-50 microm), which consist entirely of proliferating cells. After removal of dox from the incubation medium, dox fluorescence declined more efficiently in large spheroids, which led to a decreased dox toxicity as revealed by colony-forming assays. Verapamil significantly increased dox retention in large spheroids and, consequently, augmented dox toxicity. At a depth 80 microm from the spheroid periphery, a significantly decreased dox fluorescence was observed in the deep, quiescent cell layers of large spheroids. The P-glycoprotein-mediated multidrug resistance (MDR)-reversing agents verapamil, cyclosporin A, quinidine, sodium orthovanadate and tamoxifen significantly increased dox fluorescence at this depth, whereas genistein, indomethacin, probenecid and brefeldin A, which reverse multidrug-resistance-associated protein (MRP) function, exerted no effect. Anti-P-glycoprotein immunohistochemistry of multicellular tumor spheroids revealed an increase of P-glycoprotein expression in large speroids as compared to small spheroids, which was most prominent in the Ki-67-negative, quiescent cell layers 60 to 100 microm distant from the periphery of the spheroid, indicating that the MDR phenotype is related to cell quiescence. This was corroborated by whole-cell patch-clamp experiments, where the C219 antibody, which is directed against the ATP-binding site of P-glycoprotein, significantly inhibited P-glycoprotein-associated, volume-activated chloride currents in quiescent, but not proliferating cells from multicellular tumor spheroids.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Prenatal hippocampal granule cells in primary cell culture form mossy fiber boutons at pyramidal cell dendrites.

Mossy fiber boutons are the sites of synaptic signalling between hippocampal granule and pyramidal neurons. We studied the formation and localization of these terminals during development of prenatal hippocampal neurons in primary culture. Using the synaptic vesicle membrane proteins synaptophysin and synaptoporin as markers we observed that both proteins were mainly localized in perikarya and processes of fetal hippocampal neurons during the first days in vitro (DIV). Following DIV 6 synaptophysin was present in small terminals. After DIV 20 in addition large terminals immunoreactive for synaptophysin and synaptoporin were found, which were identified by electron microscopy as mossy fiber boutons impinging on pyramidal neuron dendrites. Synaptic vesicles and endosomes in the mossy fiber boutons were labeled when incubated with exogenous horseradish peroxidase, indicating that they were competent for exo-endocytosis. Taken together, our data show that hippocampal granule neurons grown in dissociated primary cultures form mossy fiber boutons containing synaptophysin and synaptoporin at pyramidal cell dendrites. Since the composition and the characteristic morphology of mossy fiber boutons formed in vitro is the same as observed in vivo we conclude that their development follows an intrinsic program.

Animals↗
PubMed1998

Doxorubicin distribution in multicellular prostate cancer spheroids evaluated by confocal laser scanning microscopy and the "optical probe technique".

Multicell-mediated drug resistance is a major impediment for the effectiveness of chemotherapeutic approaches and has been shown to be a feature of many solid tumors. We used confocal laser scanning microscopy to evaluate the depth distribution of the fluorescent cytostatic drug doxorubicin (Dox) in two size classes of multicellular cancer spheroids (MCS) (psi150+/-50 microm and 350+/-50 microm). MCS (psi150+/-50 microm) solely consist of proliferating cells, whereas in MCS (psi350+/-50 microm) peripheral proliferating cell layers are followed in the depth of the tissue by drug resistant quiescent cell areas. A technique was developed which allows noninvasively to trace fluorescence distributions down to a depth of approximately 180 microm in living MCS. This was achieved by confocal radial recordings of the mean Dox fluorescence in 600 microm2 regions of interest (ROI), equidistantly spaced (10 microm) from the center of MCS towards their periphery. The resulting fluorescence intensity profiles were subsequently corrected for absorbtion and light scattering in the depth of the tissue by a convenient algorithm. A 10 min incubation of MCS (psi150+/-50 microm) with Dox (10 microM) led to a peripheral accumulation, after 2 h Dox was homogeneously distributed within the whole MCS. In contrast, after Dox treatment of MCS (psi350+/-50 microm) for 2 h, the drug was accumulated within the peripheral proliferating cell rim of 78+/-8 microm, whereas deeper, quiescent cell layers remained unstained. When MCS were incubated with verapamil, cyclosporin A, orthovanadate, and quinidine, which are known to reverse P-glycoprotein (Pgp)-mediated multidrug resistance (MDR), Dox accumulated also in deeper cell layers. Genistein and indometacin which reverse multidrug resistance mediated by the multidrug resistance-associated protein (MRP) were without effects. The optical probe technique proved to be well suited to study MDR in a living three dimensional tissue context.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Spontaneous calcium oscillations in embryonic stem cell-derived primitive endodermal cells.

In vitro differentiation of mouse embryonic stem cells within three-dimensional cell aggregates called embryoid bodies parallels the development of postimplantation embryos at the egg cylinder stage, where visceral and parietal endoderm diverge from the primitive endoderm. We have investigated spontaneous [Ca2+]i oscillations by means of confocal laser-scanning microscopy in primitive endodermal cell layers of embryoid bodies during their differentiation to parietal and visceral endoderm. The frequency of [Ca2+]i oscillations increased from day 4 to day 19 of development, whereas their duration decreased from day 3 to days 16-17. Oscillations depended on both extracellular Ca2+ and Ca2+ release from intracellular stores as they were abolished in Ca(2+)-free solution and in the prescence of Ni2+ and thapsigargin. Signal transduction operated via the phospholipase C (PLC)-mediated inositol 1,4,5-triphosphate (InsP3) pathway with a negative feedback loop via protein kinase C (PKC) as U73,122, a blocker of PLC; bisindolylmaleimide 1, staurosporine, and H-7, blockers of PKC; and 10 mM caffeine totally inhibited [Ca2+]i spiking. Thimerosal, which hypersensitizes the InsP3 receptor, as well as vasopressin and bradykinin, which act via the InsP3 pathway, increased the frequency of [Ca2+]i spikes. In the prescence of brefeldin A (50 microM) or monensin (20 microM), which both inhibit endo/exocytotic vesicle pathways, an immediate transient increase in spiking activity was followed by a decline within 1 to 2 h. In the presence of brefeldin A or thapsigargin or in the absence of extracellular Ca2+, endocytotic vesicles were absent, suggesting that oscillating [Ca2+]i transients are involved in the exo/endocytotic vesicle shuttle.

Animals↗
PubMed1998

Hypotonic Ca2+ signaling and volume regulation in proliferating and quiescent cells from multicellular spheroids.

Hypotonicity-induced Ca2+ signals and volume regulation were studied in proliferating and quiescent subpopulations of multicellular prostate cancer spheroids. Enzymatic dissociation of multicellular spheroids 100+/-19 microm in diameter, which are entirely proliferative, yielded a population of cells with a mean cell diameter of 17.5+/-1.4 microm. After dissociation of spheroids in a size class of 200+/-30, 300+/-60, and 400+/-65 microm in diameter, two subpopulations of cells with mean cell diameters corresponding to 12.9+/-1.9 microm and 16.7+/-2 microm were discriminated. The subpopulation of large cells was shown to be proliferative by positive Ki-67 antibody staining; the subpopulation of small cells was Ki-67 negative, indicating cell quiescence. In a spheroid size class of 100+/-19 microm, a distinct subpopulation of quiescent cells was absent. Superfusion by hypotonic solutions revealed that only the proliferating cell fraction showed a regulatory volume decrease (RVD) and a [Ca2+]i transient. Both effects were absent in the quiescent cell population. The [Ca2+]i transient persisted in low (10 nM) Ca2+ solution and in the presence of 4 mM extracellular Ni2+ but was abolished in the presence of the endoplasmic reticulum Ca2+-ATPase blocker 2,5-di-tert-butyl-hydrochinone (t-BHQ). The t-BHQ likewise inhibited RVD, indicating that Ca2+ release from intracellular stores was necessary for RVD. Moreover, [Ca2+]i and RVD were dependent on an intact microfilament cytoskeleton because after 30 min of preincubation with cytochalasin B the [Ca2+]i transient was significantly reduced and RVD was abolished. The absence of RVD and [Ca2+]i transient in quiescent cells may be due to differences in the amount and the cytosolic arrangement of F-actin observed in quiescent cells.

Actins↗
PubMed1998

Prevalence of mild cognitive impairment in an elderly community sample.

The term "mild cognitive impairment" refers to cognitive deficits which exceed normal physiological aging processes, but do not fulfill the criteria for dementia. While recent studies indicate that the respective deficits can be reliably assessed, different diagnostic criteria have prevented a wide application of this diagnosis in clinical practice. The aims of the present study were (1) to assess the prevalence rates of four current diagnostic concepts and (2) to investigate mild cognitive impairment with respect to psychological and sociodemographic variables. Data from 202 probands recruited from the interdisciplinary longitudinal study on adult development were analyzed. On the time of examination, probands were between 60 to 64 years old and in a good health. The following prevalence rates were determined: 13.5% for age-associated memory impairment (AAMI), 6.5% for age-consistent memory impairment (ACMI), 1.5% for late-life forgetfulness (LLF), and 23.5% for aging-associated cognitive decline (AACD). Complaints of cognitive deficits were significantly correlated with higher scores on depression and neuroticism scales but with none of the neuropsychological measures. Reduced performance in neuropsychological tests was associated with a lower educational level and socioeconomic status. We conclude that the prevalence rates of mild cognitive impairment are highly dependent on the diagnostic criteria applied. In this respect the self-report of cognitive decline might be a less useful criteria. Longitudinal studies are warranted to further elucidate the predictive value of these diagnostic criteria.

Adult↗
PubMed1998

[Dimensions of schizophrenia in the elderly. Correlations with cognitive and motor symptoms].

In most factor analytical studies of schizophrenic symptomatology a three-factor solution was found. The aim of this study was to investigate symptomatological dimensions in old age and to clarify whether the dimensions correlate differently with neuropsychological and motor parameters. A total of 131 DSM-III-R schizophrenics (mean age 68 years) were assessed using SANS, SAPS, a neuropsychological test battery and motor scales. A factor analysis yielded three dimensions (negative, disorganized, paranoid), two of which (negative, disorganized) showed different correlations with neuropsychological and motor phenomena. Thus, three symptomatological dimensions could also be demonstrated in a chronic, old-age schizophrenic sample. The pathophysiological significance of the different correlations with neuropsychological and motor parameters should be clarified in neuroimaging and neuropathological studies.

Aged↗
PubMed1998

[Sex specific differences in hemispheric lateralization in schizophrenia? An MEG-MRI study].

In this magnetoencephalography study the issue of hemispheric lateralisation in patients with schizophrenia was addressed using acoustically evoked neuromagnetic fields. The characteristics of dipoles in the superior temporal gyrus, the primary auditory cortex, were calculated. In contrast to other studies, alterations did not concern the localisation, but rather the orientation of dipoles. Of pathophysiological interest was that the dipoles abnormalities were found left-hemispherically in male (p = 0.02) and right-hemispherically in female patients with schizophrenia (p = 0.01) when compared to controls. The findings suggest gender-specific alterations of hemispheric lateralisation in schizophrenia.

Adult↗
PubMed1998

[Mild cognitive deficit in the elderly. Results of a gerontologic study].

The term "mild cognitive impairment" refers to cognitive deficits which exceed normal physiological aging processes, but do not fulfill the criteria for dementia. The prevalence rates of four current concepts were compared in a sample of 202 healthy 60-64 year-old participants recruited from the interdisciplinary longitudinal study on adult development and aging (ILSE). Furthermore, the relationships between cognitive deficits and psychological and sociodemographic variables were examined. The following prevalence rates were determined: 13.5% for age-associated memory impairment, 6.5% for age-consistent memory impairment, 1.5% for late-life forgetfulness and 23.5% for aging-associated cognitive decline. Subjective cognitive complaints did not correlate with results obtained from neuropsychological tests. Significant correlations were however found between subjective cognitive complaints and higher scores on depression and neuroticism scales. Significant correlations were also found between a reduced test performance and a lower educational level and socioeconomic status. Longitudinal studies are warranted to further elucidate the predictive value of these diagnostic concepts.

Adult↗
PubMed1998

Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology -- a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist. The Amisulpride Study Group.

The benzamide amisulpride (ASP) is a selective D2-like dopamine antagonist, while flupentixol (FPX), a thioxanthene, blocks D2-like, D1-like and 5-HT2 receptors. To evaluate efficacy and safety of ASP and to investigate the importance of an additional D1-like antagonism for antipsychotic effects and extrapyramidal tolerability, a randomized double-blind multi- center study versus FPX as reference drug was performed for 6 weeks in 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (ASP: 1000 mg/day; FPX: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: ASP: 956 mg; FPX: 22.6 mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. The difference between the mean BPRS decreases of both treatment groups was 5.6 points (95% CI: 0.55; 10.65) in favour of ASP. According to CGI, 62% of patients in either drug group were treatment responders. ANCOVA analysis showed that reductions of BPRS (ASP: -42%; FPX: -32%) and SAPS (ASP: -78%; FPX: -65%) were more pronounced under ASP. Due to adverse events, significantly fewer ASP patients (6%) were withdrawn from the study (FPX: 18%). Extrapyramidal tolerability was better in the ASP group, as demonstrated by smaller increases in the Simpson-Angus Scale, the AIMS, and the Barnes Akathisia Scale in ANCOVA analyses with dosage as covariate. ASP appears to be as effective as FPX with regard to antipsychotic effects on positive schizophrenic symptomatology, while extrapyramidal tolerability is better. These conclusions have to be drawn cautiously, as dosage effects on outcome parameters cannot be entirely ruled out. The present results question the notion that additional blockade of D1-like receptors may be necessary to achieve sufficient antipsychotic effects or to improve extrapyramidal tolerability.

Adult↗
PubMed1998

Protein targeting in the analysis of learning and memory: a potential alternative to gene targeting.

Gene targeting using homologous recombination in embryonic stem (ES) cells offers unprecedented precision with which one may manipulate single genes and investigate the in vivo effects of defined mutations in the mouse. Geneticists argue that this technique abrogates the lack of highly specific pharmacological tools in the study of brain function and behavior. However, by now it has become clear that gene targeting has some limitations too. One problem is spatial and temporal specificity of the generated mutation, which may appear in multiple brain regions or even in other organs and may also be present throughout development, giving rise to complex, secondary phenotypical alterations. This may be a disadvantage in the functional analysis of a number of genes associated with learning and memory processes. For example, several proteins, including neurotrophins--cell-adhesion molecules--and protein kinases, that play a significant developmental role have recently been suggested to be also involved in neural and behavioral plasticity. Knocking out genes of such proteins may lead to developmental alterations or even embryonic lethality in the mouse, making it difficult to study their function in neural plasticity, learning, and memory. Therefore, alternative strategies to gene targeting may be needed. Here, we suggest a potentially useful in vivo strategy based on systemic application of immunoadhesins, genetically engineered fusion proteins possessing the Fc portion of the human IgG molecule and, for example, a binding domain of a receptor of interest. These proteins are stable in vivo and exhibit high binding specificity and affinity for the endogenous ligand of the receptor, but lack the ability to signal. Thus, if delivered to the brain, immunoadhesins may specifically block signalling of the receptor of interest. Using osmotic minipumps, the protein can be infused in a localized region of the brain for a specified period of time (days or weeks). Thus, the location and timing of delivery are controlled. Here, we present methodological details of this novel approach and argue that infusion of immunoadhesins will be useful for studying the role particular receptors play in behavioral and neural plasticity.

Animals↗
PubMed1998

Challenging the anterior attentional system with a continuous performance task: a functional magnetic resonance imaging approach.

Combining the Continuous Performance Test (CPT) with a modern functional imaging technique provides a powerful tool for investigating neurophysiological processes in the human brain. There is increasing evidence from single photon emission tomography (SPECT), positron emission tomography (PET) and presently also functional magnetic resonance imaging (fMRI) studies proposing the existence of a distributed large-scale attentional network, mediated by the dorsolateral prefrontal and mesial frontal cortex, thalamus, basal ganglia and posterior parietal and superior temporal lobe. The aim of this study is to show that fMRI is a useful tool for in vivo localization of attentional tasks and to compare the results with established imaging techniques. Functional MRI was performed on a clinical 1.5-T system using gradient-echo acquisition. For data processing, the Statistical Parametric Mapping (SPM96) package was used. A right lateralized activation pattern in the dorsolateral prefrontal and mesial frontal cortex, the thalamus and the basal ganglia was found in a group of 12 male subjects. These findings support theories suggesting right hemispheric dominance of human attention.

Adult↗
PubMed1998

31P magnetic resonance spectroscopy in the frontal lobe of major depressed patients.

Most research with 31P-magnetic resonance spectroscopy (31P-MRS) in affective disorders has been done in the field of bipolar disturbances. Reduced frontal and temporal lobe phosphomonoester (PME) concentrations were measured in the euthymic state, whereas increased values were found in the depressed state. In bipolar-II patients reduced phosphocreatine (PCr) concentrations were reported in the euthymic, depressed, and manic state. The aim of the present study was to explore whether PME and PCr were also altered in the frontal lobe of major depressed, unipolar patients. Therefore, we used 31P-MRS to investigate the relative phospholipid and high-energy phosphate concentrations in the frontal lobe of 14 unipolar patients, mostly medicated, and 8 age-matched controls. We found increased PME and decreased ATP values. Other 31P-MRS parameters were not different in both groups. Phosphomonoester percentages correlated negatively with the degree of depression. Thus, the main alterations found in bipolar depressed patients could also be demonstrated in unipolar depressed patients. The results are discussed with regard to disturbed phospholipid and intracellular high-energy phosphate metabolism in depressed patients.

Adenosine Triphosphate↗
PubMed1998

Quantification and rejection of ocular artifacts in auditory evoked fields in schizophrenics.

RESULTS: In a magnetoencephalographic investigation of the auditory evoked field (AEF) in 17 schizophrenics and 17 controls, 37% of the schizophrenics and 12% of the controls showed eye artifacts in every second trial or even more frequently. In the uncorrected average fields, the ratio between the power of artifacts and the power of the magnetoencephalogram (MEG) exceeded the value of 0.1 for 48% of the schizophrenics and for 29% of the controls. Ocular artifacts biased the locations of equivalent current dipoles of the M100 component towards deeper positions. A regression algorithm for the correction of ocular artifacts in raw data and an identification technique of ocular artifacts based on the topography of transmission coefficients is described. CONCLUSIONS: A linear dependence of ocular artifacts in AEF on the electrooculogram (EOG) was confirmed. Possible errors introduced by the correction are discussed. Transmission coefficients should be calculated for several individual trials with the same type of artifact. Errors due to evoked potentials in the EOG were found to be comparable in amplitude to noise in the AEF. Examples of transmission coefficients from the EOG to the MEG are given.

Adult↗
PubMed1998

Modified Toupet wrap for gastroesophageal reflux in childhood.

UNLABELLED: It was the aim of our study to follow up our clientele of infants and children who had undergone a partial (posterior) Toupet wrap or modified Toupet wrap. METHODS: All 22 children who had undergone a posterior partial wrap within a 4-year period were followed up for 4.0 years (0.6-5.7 years). 36.4% of children had associated anomalies such as operated esophageal atresia, operated congenital diaphragmatic hernia, Gregg's syndrome or arthrogryposis multiplex congenita. 14% of children suffered from some form of neurological impairment. Prior to operation the 4 main examinations for detection and documentation of gastroesophageal reflux (GER) disease were carried out where possible. Five children underwent Toupet fundoplication and in 17 children a modified Toupet fundoplication with reinforcement of the wrap fixation using a Vicryl-mesh was applied. A pH-metric study and upper gastrointestinal series with reflux testing were done in all 22 children at least 6 months postoperatively. Successful control of GER was documented in 21 of 22 children (95.5%). In the remaining child a reoperation was necessary to correct recurrence of a sliding hiatal hernia and GER. In three children (13.6%) postoperative complications occurred within the first 2 weeks following fundoplication and were managed medically. Following the postoperative 24-hour pH-metric study and the upper gastrointestinal series with reflux testing, one child with normal results at these investigations was lost to follow-up. The remaining 21 children were followed up for another 10 months to 5 years. Four children (18.2%) were found to suffer from functional complications (mild dumping syndrome, retrosternal pain, vomiting during episodes of asthma, dysphagia). No gas bloat syndrome occurred within the follow-up interval and all children were able to belch and vomit. There was no mortality in our limited series. Our series indicates that the partial (posterior) Toupet wrap and the modified Toupet fundoplication are safe and effective procedures for surgical correction of GER in children which preserve the ability of infants and children to belch and vomit.

Adolescent↗
PubMed1998

Cognitive stimulation with the Wisconsin Card Sorting Test: functional MR imaging at 1.5 T.

PURPOSE: To determine whether functional magnetic resonance (MR) imaging can demonstrate a specific pattern of cerebral activation during cognitive stimulation by using a high-level cognitive task such as the Wisconsin Card Sorting Test. MATERIALS AND METHODS: Thirty-one healthy volunteers underwent functional MR imaging with a 1.5-T MR imager with a standard head coil (100/50 [repetition time msec/echo time msec], 230-mm field of view, 40 degrees flip angle, 256 x 256 matrix). For stimulation, a personal computer version of the Wisconsin Card Sorting Test was used. Image analysis was done off-line, and cross-correlation coefficients between the stimulus function and the signal intensity response were calculated on a pixel-by-pixel basis and overlaid onto the corresponding anatomic MR image for each volunteer. RESULTS: Stimulation resulted in strongly frontal activation, which included the mesial and the dorsolateral prefrontal cortexes, interconnected with Brodmann areas 44, 45, and 46. While activation was often bilateral, the largest area of activation was in the right hemisphere. Activation also was found in the basal ganglia and the mesial thalamic nuclei. CONCLUSION: Functional MR imaging can demonstrate a specific pattern during activation with a cognitive task. Functional MR imaging has promise for more precise anatomic and functional imaging studies of brain interaction than have other imaging modalities.

Adult↗