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Biomedical subjects

T Dierks

Publications and source records attributed to T Dierks.

At least 73 records · Page 4Linked to original sources
PubMed1994

[Ketamine racemate versus S-(+)-ketamine with or without antagonism with physostigmine. A quantitative EEG study on volunteers].

The potency of S-(+)-ketamine is approximately double that of the racemic ketamine. This study was carried out to investigate the recovery of cerebral electrical function after a bolus of 1.3 mg/kg ketamine or 0.65 mg/kg S-(+)-ketamine and subsequent continuous application of 4 mg/kg h ketamine per h or 2 mg/kg S-(+)-ketamine, per h for 15 min. Furthermore, the centrally acting, cholinergic agonist physostigmine has been reported to antagonize ketamine and to shorten the recovery period. Therefore, after S-(+)-ketamine 0.012 mg/kg physostigmine was tested against saline placebo. METHODS. With their own informed consent and the approval of the ethics committee 12 healthy volunteers were enrolled in a double-blind cross-over study. All drugs were dissolved in identical volumes. On three dates with intervals of at least 1 week between, ketamine/NaCl, S-(+)-ketamine/physostigmine or S-(+)-ketamine/NaCl was administered (Table 1). The sequence was randomized. The EEG was recorded from 20 sites according to the 10/20 system and after Fast-Fourier transformation computed into amplitudes within the delta, theta, alpha, and beta bands and within the total spectrum. The median, the spectral edge frequency and the dominant frequency (dF) were also determined. Mean values of all electrodes before and at 10, 15, 30, 45 and 195 min after the bolus injection were compared using two-dimensional analysis of variance (ANOVA, significance level P < 0.05). RESULTS. The characteristic increase in theta-amplitude and decrease of alpha-amplitude were observed after ketamine and S-(+)-ketamine. Median and dF dropped from the alpha to the theta frequency range. Ketamine led to a greater increase in total, delta, theta and beta amplitude during anaesthesia. 3 hours after ketamine/S-(+)-ketamine anaesthesia a significant decrease in the median and dominant frequency and in total, delta, theta, alpha and beta amplitudes confirmed residual impairment of cerebral function after all study drugs. No differences were found between physostigmine and placebo. DISCUSSION. The EEG changes during ketamine/S-(+)-ketamine administration suggest a slightly deeper anaesthetic level after ketamine. The course of recovery was not different after ketamine and after S-(+)-ketamine. The spectral edge frequency did not differ between measurement points, and is therefore not suitable for assessment of the depth of anaesthesia reached with ketamine/S-(+)-ketamine. The dose of physostigmine tested was probably too low to produce antagonism of S-(+)-ketamine. An increased dosage of physostigmine has yet to be studied, but is likely to cause a higher rate of side effects, such as nausea, vomiting and bradycardia, and possibly even tonic-clonic seizures.

Adolescent↗
PubMed1993

Kinetic characterization of the reconstituted dicarboxylate carrier from mitochondria: a four-binding-site sequential transport system.

The mitochondrial antiport carriers form a protein family with respect to their structure and function. The kinetic antiport mechanism, being of the sequential type, shows that the dicarboxylate carrier also belongs to this family. This was demonstrated by bireactant initial velocity studies of the purified and reconstituted carrier protein. The transport affinity of the carrier for the internal substrate was largely independent of the external substrate concentration and vice versa, whereas the carrier's apparent Vmax rose with increasing saturation of internal and external binding sites. Thus, the carrier forms a catalytic ternary complex with one internal and one external substrate molecule. As compared to other mitochondrial antiport carriers, however, the situation with the dicarboxylate carrier is more complex. On each membrane side of the protein two separate binding sites exist, one specific for phosphate (or its analogue phenyl phosphate), the other specific for dicarboxylate (or butyl malonate), that can be occupied by the respective substrates without mutual interference. This became evident from the non-competitive interaction of these substrates (or analogues) with the carrier. The two external, but not the two internal binding sites could be saturated simultaneously with phosphate and malate, thereby causing inhibition of transport. All four binding sites must be associated with the same translocation pathway through the carrier protein, since the sequential antiport mechanism held true for the phosphate/malate heteroexchange as well as for the malate/malate or phosphate/phosphate homoexchange.

Animals↗
PubMed1993

Reaction mechanism of the reconstituted tricarboxylate carrier from rat liver mitochondria.

Transport of citrate and malate by the tricarboxylate carrier from rat liver mitochondria has been studied in a reconstituted system. Homologous citrate/citrate antiport and heterologous (electroneutral) citrate/malate antiport was kinetically analyzed. The maximal rates of the two exchange modes did not vary significantly within pH 7.0 to 7.8 which is the optimum pH-range for transport activity. On the other hand, the apparent transport affinity varied considerably within this range. Calculations on the basis of the different pK values for citrate and malate indicate that only H-citrate2- and malate2- are accepted as transport species by the tricarboxylate carrier. A complete set of half-saturation constants was established for citrate and malate on both the external and the internal side of the membrane. Both the Km and Vmax for citrate and malate were independent of the nature of the countersubstrate at the other side of the membrane. Bisubstrate initial velocity analyses of the exchange reaction resulted in a kinetic pattern which is consistent with a sequential antiport mechanism. This type of mechanism implies formation of a ternary complex of the carrier with two substrate molecules before the transport reaction occurs. Thus the tricarboxylate carrier falls into the functional family of mitochondrial carrier proteins showing sequential transport mechanisms.

Animals↗
PubMed1993

The role of molecular chaperones in protein transport into the endoplasmic reticulum.

In eukaryotic cells export of the vast majority of newly synthesized secretory proteins is initiated at the level of the membrane of the endoplasmic reticulum (microsomal membrane). The precursors of secretory proteins are not transported across the microsomal membrane in their native state. Typically, signal peptides in the precursor proteins are involved in preserving the transport-competent state. Furthermore, there are two alternatively acting mechanisms involved in preserving transport competence in the cytosol. The first mechanism involves two ribonucleoparticles (ribosome and signal recognition particle) and their receptors on the microsomal surface and requires the hydrolysis of GTP. The second mechanism does not involve ribonucleoparticles and their receptors but depends on the hydrolysis of ATP and on cis-acting molecular chaperones, such as heat shock cognate protein 70 (hsc 70). In both mechanisms a translocase in the microsomal membrane mediates protein translocation. This translocase includes a signal peptide receptor on the cis-side of the microsomal membrane and a component that also depends on the hydrolysis of ATP. At least in certain cases, an additional nucleoside triphosphate-requiring step is involved which is related to the trans-acting molecular chaperone BiP.

Adenosine Triphosphate↗
PubMed1993

Equivalent dipoles of FFT data visualize drug interaction at benzodiazepine receptors.

The aim of the present investigation was to study if the benzodiazepine receptor antagonist flumazenil could reverse the effects on the brain electrical activity induced by the benzodiazepine receptor agonist midazolam. The method of FFT approximation was used for this purpose. It allows the calculation of center of gravity equivalent dipoles of spectral EEG data. The results are reference independent and allow therefore a more unambiguous interpretation compared to conventional FFT data reports. Twelve subjects were investigated before and after 0.1 mg/kg and 0.2 mg/kg midazolam respectively, directly and 4 h after administration of 1 mg flumazenil. Our results imply that the application of flumazenil after midazolam sedation leads to an almost complete restoration of the brain electrical activity. However, especially in the beta frequencies above 20 Hz differences in depth of equivalent dipoles were found directly after flumazenil application as well as 4 h later. This could suggest that neuronal generators in different brain structures were responsible for the electrical activity after flumazenil administration compared to before.

Adult↗
PubMed1993

Brain electrical activity in depression described by equivalent dipoles.

The majority of neurophysiological investigations of waking EEG in depression have been relatively disappointing. Since the topographic distribution of brain electrical activity over the scalp in the frequency domain (FFT-power) varies considerably when choosing another site for the reference, it is not surprising that various investigators reported contradictory results. The aim of the present study was to investigate differences in brain electrical activity in a sample of depressed patients as compared to healthy subjects using a newly developed method called FFT approximation. As the major finding healthy subjects and depressed patients demonstrated significantly divergent patterns of localization between frequency bands in the anterior-posterior direction. The investigation suggests that a non-invasive neurophysiological methods gives results which are comparable to those obtained by other functional and structural imaging methods in depressive illness.

Adolescent↗
PubMed1993

Age-related changes of spontaneous EEG described by equivalent dipoles.

One of the most commonly used methods for quantification of an EEG is Fast Fourier Transformation (FFT), which suffers from some serious disadvantages, for example: FFT-power data are highly dependent on the choice of reference and thus the topographical distribution of FFT-power data varies according to the used reference. Novel methods which partly resolve this problem have been developed. These methods provide unambiguous data in the frequency domain with regard to reference. In comparison to conventional FFT-power data this approach allows to a higher degree to draw topographical valid conclusions regarding brain function. The aim of the present study on brain electrical activity, using the method of FFT approximation, was to investigate age-related alterations of brain function in carefully screened healthy subjects. The major finding was that, except for a more superficially located beta-activity of higher strength with increasing, age no age-related changes in electrical brain activity were observed.

Adult↗
PubMed1993

Dementia of the Alzheimer type: effects on the spontaneous EEG described by dipole sources.

The present study on brain electrical activity in healthy subjects (n = 35) and patients suffering from dementia of the Alzheimer type (DAT; n = 35) used Fast Fourier Transformation-dipole approximation to quantify differences between the two groups. DAT patients showed a shift of alpha and beta activity toward frontal brain regions. The amount of this shift correlated with the degree of dementia. The relative distribution of magnitude of activity between the frequency bands differed between DAT patients and control subjects. DAT patients had higher magnitudes in the slow frequency range, correlating with the severity of dementia, and lower ones in the alpha and beta range compared with findings in age-matched control subjects.

Aged↗
PubMed1993

Differences in P300 amplitudes and topography between cycloid psychosis and schizophrenia in Leonhard's classification.

In a polydiagnostic approach, we investigated the parameters of auditory P300 in a group of 18 remitted schizophrenics and in 18 age- and sex-matched controls. All patients fulfilled the criteria of schizophrenic disorder according to DSM-III-R. Applying Leonhard's classification, patients were to be subdivided into 7 cycloid psychosis and 11 Leonhard's schizophrenics. Patients with cycloid psychosis fulfilled the operational criteria of Brockington et al. We found significantly lower P300 amplitudes in the group of Leonhard's schizophrenics than in controls and in cycloid psychosis, whereas no difference could be shown between patients with cycloid psychosis and controls. Both the maxima and the minima of the P300 field map were dislocated significantly to the right in the group of Leonhard's schizophrenics but not in cycloid psychosis.

Adult↗
PubMed1993

Amplitudes of auditory P300 in remitted and residual schizophrenics: correlations with clinical features.

The parameters of auditory P300 were studied with reference-independent methods in a group of 18 remitted and residual schizophrenics, and in 18 age- and sex-matched controls. In the schizophrenic group, significant inverse correlations were found between P300 amplitudes and level of psychopathology assessed with the Scale for Assessment of Negative Symptoms and with the Brief Psychiatric Rating Scale. Clinical variables regarding social functioning and adaptation, assessed with the Schedule for Affective Disorders and Schizophrenia, and with axis V of DSM-III-R, correlated significantly with low amplitudes. The scalp locations of the maxima and minima of the P300 potentials had the tendency to be dislocated to the right in schizophrenics compared with controls. The results indicate low P300 amplitudes to be associated with pervasive cognitive impairment. Future studies will determine whether low P300 amplitudes have prognostic validity for course and outcome of schizophrenic disorders.

Acoustic Stimulation↗
PubMed1993

Segmentation of the spontaneous EEG in dementia of the Alzheimer type.

Studies on EEG data in dementia of the Alzheimer type have mainly investigated parameters in the frequency domain. However, the EEG also reflects the momentary functional state of the brain. The EEG can be partitioned into segments of spatially stationary map landscapes as characterized by the locations of potential maxima and minima, to study the time domain of the EEG. We calculated the segment structure of 19-channel EEG recordings (1-30 Hz) from 10 patients with dementia of the Alzheimer type and 10 sex-matched geriatric controls. The EEG maps corresponding to global field power peaks were used for analysis. The locations of the potential maximum and minimum of the maps were determined over the course of 20 s and used for segmentation. The segments of EEG activity were significantly fewer (p < 0.05) and the segments lasted longer (p < 0.05) in patients compared to controls. This effect could be observed over the whole period of recording and thus was not caused by only a few long segments. The data may be linked to morphological and biochemical findings of neuronal loss and loss of synapses in dementia of the Alzheimer type.

Aged↗
PubMed1993

[Progressive paralysis: prognostic indications by modern imaging procedures. A case report].

The case of a patient with early diagnosed neurosyphilis (general paresis) is presented. Modern neuroimaging techniques such as single photon emission computed tomography (SPECT) may give clues to the treatment outcome as early as 1 month after antibiotic treatment. Improvement of cognitive functions was accompanied by normalization of the initially altered P300-topography.

Brain Mapping↗
PubMed1992

The mitochondrial carnitine carrier: characterization of SH-groups relevant for its transport function.

The transport function of the purified and reconstituted carnitine carrier from rat liver mitochondria was correlated to modification of its SH-groups by various reagents. The exchange activity and the unidirectional transport, both catalyzed by the carnitine carrier, were effectively inhibited by N-ethylmaleimide and submicromolar concentrations of mercurial reagents, e.g., mersalyl and p-(chloromercuri)benzenesulfonate. When 1 microM HgCl2 or higher concentrations of the above mentioned mercurials were added, another transport mode of the carrier was induced. After this treatment, the reconstituted carnitine carrier catalyzed unidirectional substrate-efflux and -influx with significantly reduced substrate specificity. Control experiments in liposomes without carrier or with inactivated carrier protein proved the dependence of this transport activity on the presence of active carnitine carrier. The mercurial-induced uniport correlated with inhibition of the 'physiological' functions of the carrier, i.e., exchange and substrate specific unidirectional transport. The effect of consecutive additions of various reagents including N-ethylmaleimide, mercurials, Cu(2+)-phenanthroline and diamide on the transport function revealed the presence of at least two different classes of SH-groups. N-Ethylmaleimide blocked the carrier activity by binding to SH-groups of one of these classes. At least one of these SH-groups could be oxidized by the reagents forming S-S bridges. Besides binding to the class of SH-groups to which N-ethylmaleimide binds, mercurials also reacted with SH-groups of the other class. Modification of the latter led to the induction of the efflux-type of carrier activity characterized by loss of substrate specificity.

Animals↗
PubMed1992

Probing the active site of the reconstituted aspartate/glutamate carrier from mitochondria. Structure/function relationship involving one lysine and two cysteine residues.

Treatment of the reconstituted aspartate/glutamate carrier from mitochondria with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (Nbd-Cl) led to complete inactivation of carrier function. Inhibition could be attributed to chemical modification of one single cysteine in the active site. This residue was specifically protected in the presence of aspartate or glutamate, 50% substrate protection being observed at half-saturation of the external binding site. The bifunctional reagent 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS) also modified the same cysteine and, in addition, an active-site lysine identified previously [Dierks, T., Stappen, R., Salentin, A. & Krämer, R. (1992) Biochim. Biophys. Acta 1103, 13-24]. The proximity of the cysteine [Cys(a)] and the lysine residue was confirmed by a mutual exclusion of the respective reagents when added consecutively. By using a variety of reagents a further cysteine [Cys(b)] and probably a histidine residue could be discriminated from Cys(a) and the lysine. The applied reagents were classified according to functional and structural criteria. Class A reagents, like Nbd-Cl, modified the active-site Cys(a) thereby inhibiting the antiport function. Class B reagents, like HgCl2, reacted with both Cys(a) and Cys(b) leading to a conversion of the carrier from antiport to uniport function [Dierks, T., Salentin, A., Heberger, C. & Krämer, R. (1990) Biochim. Biophys. Acta 1028, 268-280]. DIDS at relatively high concentration (60 microM) also acted as a uniport inducer. Class C reagents finally, like pyridoxal phosphate or diethyl pyrocarbonate, modified the active-site lysine or histidine, respectively, and blocked antiport and uniport activity. By testing the accessibility of the mentioned residues to the various reagents, when applied in different order, topological relationships could be elaborated indicating the location of these amino acids with respect to the exofacial active site of the carrier protein.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Probing the active site of the reconstituted aspartate/glutamate carrier from bovine heart mitochondria: carbodiimide-catalyzed acylation of a functional lysine residue.

Upon modification of the reconstituted aspartate/glutamate carrier by various amino acid-reactive chemicals a functional lysine residue at the exofacial binding site was identified. The inactivation of transport function by the lysine-specific reagents pyridoxal phosphate (PLP, IC50 400 microM) and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS, IC50 300 microM) could specifically be suppressed by the substrates aspartate and glutamate; a 50% substrate protection was observed at half-saturation of the external binding site. The same held true for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, IC50 500 microM) and diethyl pyrocarbonate (DEPC, IC50 20 microM), two reagents known to modify carboxylic or histidinyl side-chains, respectively. EDC, however, turned out to catalyze an acylation of the active site lysine by activating carboxyls that had to be present in the incubation medium. This special mechanism, which was proven by protein labelling using EDC/[14C]succinate, necessitates a lysine side-chain of high reactivity and low pK, since the modification had to occur at pH less than or equal to 6.5, i.e. not too far from the pK of the carboxyl to be activated. All reagents applied, additionally including 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS, IC50 10 microM), were effective at this pH. Competition experiments revealed interaction of EDC, PLP, SITS and probably DIDS at the same active site lysine. For DEPC a lysine modification could not be ruled out. Yet, a model comprising a histidine juxtaposed to the lysine seems to be appropriate.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1992

Equivalent EEG sources determined by FFT approximation in healthy subjects, schizophrenic and depressive patients.

In recent years, as a result of increasing calculation power of computers and with the aid of appropriate computer programs it has been made possible to calculate equivalent dipoles as intracranial representations of cerebral electrical activity. The present study investigated the localization of intracerebral equivalent dipoles in healthy controls and psychiatric patients. The equivalent dipole sources were calculated for conventional frequency bands of the background EEG. This was performed using the FFT approximation by Lehmann and Michel. Results showed more anterior equivalent sources for alpha and beta activity in all patients compared to controls. The beta activity was also generated in deeper brain structures in controls compared to patients. These results indicate that frequency bands may be generated in different brain structures in patients suffering from psychiatric diseases as compared to healthy controls and that the calculation of equivalent dipole sources may be a way to perform a sensible and substantial data reduction.

Adult↗