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M Frings

Publications and source records attributed to M Frings.

15 recordsLinked to original sources
PubMed2006

Activation of cerebellar nuclei comparing finger, foot and tongue movements as revealed by fMRI.

The aim of the present study was to compare possible activation of the interposed and dentate cerebellar nuclei during finger, foot and tongue movements using functional magnetic resonance imaging (fMRI). Nineteen healthy control subjects performed sequential finger and repetitive tongue and foot movement tasks. Thin slices (2.5mm) were acquired of the cerebellar region containing the cerebellar nuclei with high spatial resolution (matrix size 128 x 128 x 10) using a Siemens 1.5T Sonata system. Use of an eight channel head coil provided better signal-to-noise-ratio compared to standard head coils. Only data of those 12 subjects were included in final statistical analysis, who showed significant activation of the cerebellar nuclei at least in one task. Cortical activations of the superior cerebellum were found in accordance to the known somatotopy of the human cerebellar cortex. Nuclear activations were most significant in the sequential finger movement task. Both interposed nuclei and ipsilateral dentate nucleus were activated. Dentate activation was present in the more caudal parts of both the dorsal and ventral nucleus. Activation overlapped with motor and non-motor domains of the dentate nucleus described by Dum and Strick [R.P. Dum, P.L. Strick, An unfolded map of the cerebellar dentate nucleus and its projections to the cerebral cortex, J. Neurophysiol. 89 (2003) 634-639] based on anatomical data in monkey. Tongue movement related activations were less extensive and overlapped with activations of caudal parts of the dentate nucleus in the finger movement task. No nuclear activation was seen following foot movements. The present findings show that both interposed and dentate nuclei are involved in sequential finger movements in humans. Interposed nucleus likely contributes to movement performance. Although no direct conclusions could be drawn based on the present data, different parts of the dentate nucleus may contribute to movement performance, planning and possible non-motor parts of the task.

Adult↗
PubMed2005

Probabilistic 3D MRI atlas of the human cerebellar dentate/interposed nuclei.

In a previous study, a three-dimensional (3D) MRI atlas of the human cerebellar nuclei was introduced based on findings in one healthy human subject [Dimitrova, A., Weber, J., Redies, C., Kindsvater, K., Maschke, M., Kolb, F.P., Forsting, M., Diener, H.C., Timmann, D., 2002. MRI atlas of the human cerebellar nuclei. NeuroImage 17, 240-255]. The present MRI investigation was designed to study variability of the anatomy of the dentate/interposed nuclei in a larger group of healthy subjects. Similar to our previous study, iron-induced susceptibility artifacts were used to visualize the cerebellar nuclei as hypointensities on MR images. Data of 63 healthy subjects (27 female, 36 male; mean age 45.3+/-13.4 years, age range 22--71 years) were included. A 3D axial volume of the cerebellum was acquired using a T2*-weighted FLASH sequence on a Siemens Sonata 1.5 T MR scanner. Each volume was registered, re-sampled to 1.00 x 1.00 x 1.00 mm(3) voxel size and spatially normalized into a standard proportional stereotaxic space using SPM99. Dentate/interposed nuclei were traced on axial images and saved as regions of interest using MRIcro-software by two independent examiners. A probabilistic 3D MRI atlas of the cerebellar dentate/interposed nuclei is presented based on findings in all subjects.

Adolescent↗
PubMed2004

Eyeblink conditioning in patients with hereditary ataxia: a one-year follow-up study.

Delay eyeblink conditioning was examined in patients with genetically-defined heredoataxias and age-matched control subjects. 24 patients with spinocerebellar ataxia type 6 (SCA6), type 3 (SCA3), and Friedreich's ataxia (FRDA) participated. SCA6 affects primarily the cerebellum, whereas extracerebellar involvement is common in SCA3 and FRDA. Testing was performed in three sessions six months apart. Severity of ataxia was defined based on the International Ataxia Cooperative Rating Scale (ICARS). As expected, cerebellar patients were significantly impaired in eyeblink conditioning compared to controls. Signs of retention and further learning across sessions were present in controls, but not in the cerebellar patients. In addition, findings of disturbed timing of conditioned responses were observed. Both onsets and peaks of the conditioned responses (CRs) occurred significantly earlier in cerebellar patients. Shortened CR responses were most prominent in patients with primarily cerebellar cortical disease (SCA6). In the group of all cerebellar patients, the SCA3 and the FRDA group correlations between learning deficits and clinical findings were weak. Moderate-to-strong correlations were found in the SCA6 patients. There was no significant change, however, in clinical ataxia scores and CR incidence across the three sessions. In summary, impaired learning of conditioned eyeblink responses is a stable finding across multiple sessions in patients with degenerative cerebellar disorders. Eyeblink conditioning may be a useful measure of cerebellar impairment in patients with hereditary ataxias that primarily affect the cerebellum (such as SCA6). In other heredoataxias (such as SCA3 and FRDA), extracerebellar involvement not assessed by ICARS likely contributes to eyeblink conditioning abnormalities.

Adult↗
PubMed2001

Spirodienone derivatives of a spherand-type calixarene.

Oxidation of the spherand-type calixarene 4 with 1 or 2 equiv of phenyltrimethylammonium tribromide/base afforded mono- and bis(spirodienone) derivatives (8b and 9, respectively). The spirodienone groups are derived from the oxidation of two phenols connected by a common methylene group. NOESY data indicated that 9 possesses a "head to tail" arrangement of the spirodienone groups. Oxidation of 4 with 3 equiv of the oxidizing reagent afforded two tris(spirodienone) calixarene derivatives 11 and 10 with C(1) and C(3) symmetries, respectively. The same tris(spirodienone) products were obtained by oxidation of 9 with I(2)/aq KOH. Tris(spirodienone) 11 displayed NOE cross-peaks in the NOESY NMR spectrum consistent with a nonalternant disposition of carbonyl and ether groups. Upon heating 10 and 11 isomerize in the solid state and in solution. The major component in the equilibration mixtures is 11, indicating that this is the thermodynamically more stable tris(spirodienone) isomer.

Journal Article↗
PubMed2001

Stereochemistry of a spherand-type calixarene.

The stereochemistry of the spherand-type calixarene 2a is analyzed in terms of the configuration of the three 2,2'-dihydroxybiphenyl subunits (R or S) and the disposition of the methylene groups (crown or twist). X-ray crystallography indicates that the neutral 2a and its mono- or dianion (in form of the salts 2a(-) x C(5)H(5)NH(+) and 2a(2)(-) x 2Et(3)NH(+)) exist essentially in the same conformation (RRS/SSR-twist). This asymmetric RRS/SSR-twist form is the lowest energy conformer according to molecular mechanics calculations. Low-temperature (1)H NMR data indicate the presence of a major conformer of C(1) symmetry, in agreement with a RRS/SSR-twist form. The lowest energy topomerization pathway mutually exchanges two pairs of methylene protons and is ascribed to an enantiomerization process involving rotation around an Ar-Ar bond.

Journal Article↗
PubMed2001

Rac and phosphatidylinositol 3-kinase regulate the protein kinase B in Fc epsilon RI signaling in RBL 2H3 mast cells.

FcepsilonRI signaling in rat basophilic leukemia cells depends on phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase Rac. Here, we studied the functional relationship among PI3-kinase, its effector protein kinase B (PKB), and Rac using inhibitors of PI3-kinase and toxins inhibiting Rac. Wortmannin, an inhibitor of PI3-kinase, blocked FcepsilonRI-mediated tyrosine phosphorylation of phospholipase Cgamma, inositol phosphate formation, calcium mobilization, and secretion of hexosaminidase. Similarly, Clostridium difficile toxin B, which inactivates all Rho GTPases including Rho, Rac and Cdc42, and Clostridium sordellii lethal toxin, which inhibits Rac (possibly Cdc42) but not Rho, blocked these responses. Stimulation of the FcepsilonRI receptor induced a rapid increase in the GTP-bound form of Rac. Whereas toxin B inhibited the Rac activation, PI3-kinase inhibitors (wortmannin and LY294002) had no effect on activation of Rac. In line with this, wortmannin had no effect on tyrosine phosphorylation of the guanine nucleotide exchange factor Vav. Wortmannin, toxin B, and lethal toxin inhibited phosphorylation of PKB on Ser(473). Similarly, translocation of the pleckstrin homology domain of PKB tagged with the green fluorescent protein to the membrane, which was induced by activation of the FcepsilonRI receptor, was blocked by inhibitors of PI3-kinase and Rac inactivation. Our results indicate that in rat basophilic leukemia cells Rac and PI3-kinase regulate PKB and suggest that Rac is functionally located upstream and/or parallel of PI3-kinase/PKB in FcepsilonRI signaling.

Animals↗
PubMed2000

G protein-coupled receptor-induced sensitization of phospholipase C stimulation by receptor tyrosine kinases.

Activation of stably expressed M(2) and M(3) muscarinic acetylcholine receptors (mAChRs) as well as of endogenously expressed lysophosphatidic acid and purinergic receptors in HEK-293 cells can induce a long lasting potentiation of phospholipase C (PLC) stimulation by these and other G protein-coupled receptors (GPCRs). Here, we report that GPCRs can induce an up-regulation of PLC stimulation by receptor tyrosine kinases (RTKs) as well and provide essential mechanistic characteristics of this sensitization process. Pretreatment of HEK-293 cells for 2 min with carbachol, a mAChR agonist, lysophosphatidic acid, or ATP, followed by agonist washout, strongly increased (by 2-3-fold) maximal PLC stimulation (measured >/=40 min later) by epidermal growth factor and platelet-derived growth factor, but not insulin, and largely enhanced PLC sensitivity to these RTK agonists. The up-regulation of RTK-induced PLC stimulation was cycloheximide-insensitive and was observed for up to approximately 90 min after removal of the GPCR agonist. Sensitization of receptor-induced PLC stimulation caused by prior M(2) mAChR activation was fully prevented by pertussis toxin and strongly reduced by expression of Gbetagamma scavengers. Furthermore, inhibition of conventional protein kinase C (PKC) isoenzymes and chelation of intracellular Ca(2+) suppressed the sensitization process, while overexpression of PKC-alpha, but not PKC-betaI, further enhanced the M(2) mAChR-induced sensitization of PLC stimulation. None of these treatments affected acute PLC stimulation by either GPCR or RTK agonists. Taken together, short term activation of GPCRs can induce a strong and long lasting sensitization of PLC stimulation by RTKs, a process apparently involving G(i)-derived Gbetagammas as well as increases in intracellular Ca(2+) and activation of a PKC isoenzyme, most likely PKC-alpha.

Adenosine Triphosphate↗
PubMed2000

Multiple action sites of flufenamate on ion transport across the rat distal colon.

The antisecretory effects of flufenamate in the rat distal colon were investigated with the Ussing-chamber and the patch-clamp method as well as by measurements of the intracellular Ca(2+) concentration using fura-2-loaded isolated crypts. Flufenamate (5.10(-4) mol l(-1)) suppressed the short-circuit current (Isc) induced by carbachol (5.10(-5) mol l(-1)), forskolin (5.10(-6) mol l(-1)) and the Isc induced by the membrane-permeable analogue of cyclic AMP, CPT - cyclic AMP (10(-4) mol l(-1)). Indomethacin (10(-6) - 10(-4) mol l(-1)) did not mimic the effect of flufenamate, indicating that the antisecretory effect of flufenamate is not related to the inhibition of the cyclo-oxygenase. When the basolateral membrane was depolarized by a high K(+) concentration and a Cl(-) current was induced by a mucosally directed Cl(-) gradient, the forskolin-stimulated Cl(-) current was blocked by flufenamate, indicating an inhibition of the cyclic AMP-stimulated apical Cl(-) conductance. When the apical membrane was permeabilized by the ionophore, nystatin, flufenamate decreased the basolateral K(+) conductance and inhibited the Na(+) - K(+)-ATPase. Patch-clamp experiments revealed a variable effect of flufenamate on membrane currents. In seven out of 11 crypt cells the drug induced an increase of the K(+) current, whereas in the remaining four cells an inhibition was observed. Experiments with fura-2-loaded isolated crypts indicated that flufenamate increased the basal as well as the carbachol-stimulated intracellular Ca(2+) concentration. These results demonstrate that flufenamate possesses multiple action sites in the rat colon: The apical Cl(-) conductance, basolateral K(+) conductances and the Na(+) - K(+)-ATPase.

Animals↗
PubMed2000

Spontaneous contractions of intestinal smooth muscle re-aggregates from the new-born rat triggered by thromboxane A2.

Isolated smooth muscle cells from the small intestine of new-born rats were prepared by enzymatic digestion. These cells re-aggregate after 1 day in culture to clusters. The re-aggregates show spontaneous rhythmical contractions at 37 degrees C with a frequency (13.1 +/- 0.8 min-1, n = 49), which is similar to that of the intact smooth muscle layer. The cholinergic agonist carbachol (5 x 10(-5) mol l-1) caused an increase in the frequency of the spontaneous contractions often ending in a permanent contraction. A similar effect was achieved with the thromboxane A2 (TXA2) agonist, U-46619 (10(-5) mol l-1). In contrast, both the TXA2 receptor blocker, Bay u3405 (5 x 10(-4) mol l-1), as well as the Ca2+ channel blocker, verapamil (5 x 10(-5) mol l-1), suppressed the spontaneous contractions. The observed contractility was insensitive against the neuronal blocker tetrodotoxin (10(-6) mol l-1). These analyses of video images were supported by the measurement of relative changes in the intracellular Ca2+ concentration with the Ca(2+)-sensitive dye, fura-2. Spontaneous contractions were paralleled by spikes in the intracellular Ca2+ concentration, which were abolished by Bay u3405, but stimulated by U-46619 or carbachol. In summary, these results obtained at re-aggregates of intestinal smooth muscle cells support the hypothesis of a role of TXA2 in the generation of spontaneous intestinal smooth muscle contractions in vitro.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Electrogenic Ca2+ entry in the rat colonic epithelium.

Capacitative Ca2+ entry in isolated rat colonic crypts was induced by dialysing the cells in the whole-cell patch-clamp mode with a pipette solution having a high Ca(2+)-buffering capacity. Under these conditions crypt cell resting potential was lower than normal. Flufe-namate, La3+ and Gd3+, blockers of non-selective cation channels, hyperpolarized the crypt cells and decreased membrane current. This current exhibited a cation selectivity of Na+>Ca2+. In contrast to Na+, Ca(2+) inhibited the current at concentrations exceeding 1 mmol/l. Indirect evidence suggests that the non-selective cation conductance is activated after stimulation of muscarinic receptors. Carbachol, a cholinergic agonist, evoked a transient hyperpolarization and an increase in membrane outwards current. The half-time of the decay of the carbachol response was shortened strongly in the presence of La3+. Fura-2 experiments with isolated crypts confirmed that La3+ inhibited the carbachol-induced increase in intracellular Ca2+. In parallel Ussing chamber experiments, La3+ suppressed the induction of Cl- secretion by carbachol. These results demonstrate that a non-selective cation conductance activated by store depletion may be involved in the regulation of electrolyte transport by agonists of the Ca2+ signalling pathway.

Animals↗
PubMed1994

[Effect of the prostacyclin analog taprostene on ischemic ST-segment depression in the stress ECG of coronary patients].

Prostaglandins and prostacyclin are potent vasodilators with marked hemodynamic effects, i.e., both improve cardiac function and possibly cause myocardial ischemia. In order to assess the stable prostacyclin analogon taprostene (T) we first performed an open preliminary study with increasing T-doses (6.5-50 ng/kg/min) and, secondly a double-blind crossover study versus placebo to investigate its influence on ischemic ST-segment depression during exercise stress testing under continuous T-infusions of 25 ng/kg/min (in one case 12.5 ng/kg/min). Eleven of 12 normotensive male patients (age 40 to 60, mean 52.8 +/- 8.4 years) suffering from angiographically proven coronary heart disease and stable angina pectoris completed the study. T was well tolerated, even under increasing doses, and blood pressure and the ECG parameters did not change. The double-blind study revealed no variation in the extent of ischemic ST-segment depression when compared to placebo, and all other ECG parameters as well as the blood pressure remained unaffected. Thus, myocardial ischemia cannot be ruled out completely under T, but earlier clinical findings may be confirmed characterizing T as a marked cytoprotective agent and, to a less degree, as a potent vasodilator.

Adult↗