Biomedical subjects

N König

Publications and source records attributed to N König.

At least 19 recordsLinked to original sources

PubMed2004

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Clinical Trials as Topic↗

PubMed2003

Neuronal mechanism of nociceptin-induced modulation of learning and memory: involvement of N-methyl-D-aspartate receptors.

Nociceptin (also called orphanin FQ) is an endogenous heptadecapeptide that activates the opioid receptor-like 1 (ORL1) receptor. Nociceptin system not only affects the nociception and locomotor activity, but also regulates learning and memory in rodents. We have previously reported that long-term potentiation and memory of ORL1 receptor knockout mice are enhanced compared with those in wild-type mice. Here, we show the neuronal mechanism of nociceptin-induced modulation of learning and memory. Retention of fear-conditioned contextual memory was significantly enhanced in the ORL1 receptor knockout mice without any changes in cued conditioned freezing. Inversely, in the wild-type mice retention of contextual, but not cued, conditioning freezing behavior was suppressed by exogenous nociceptin when it was administered into the cerebroventricle immediately after the training. ORL1 receptor knockout mice exhibited a hyperfunction of N-methyl-D-aspartate (NMDA) receptor, as evidenced by an increase in [3H]MK-801 binding, NMDA-evoked 45Ca2+ uptake and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity and its phosphorylation as compared with those in wild-type mice. The NMDA-induced CaMKII activation in the hippocampal slices of wild-type mice was significantly inhibited by exogenous nociceptin via a pertussis toxin-sensitive pathway. However, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor GluR1 subunit at Ser831 and Ser845, and NMDA receptor subunit NR2B at Thr286 were phosphorylated similarly after NMDA receptor stimulation in both type of mice. The expressions of GluR1 and GluR2 also did not change, but the levels of polysialylated form of neuronal cell adhesion molecule (N-CAM) were reduced in the ORL1 receptor knockout as compared with wild-type mice. These results suggest that nociceptin system negatively modulates learning and memory through the regulation of NMDA receptor function and the expression of N-CAM.

Animals↗

PubMed2001

Measurement of ataxic symptoms with a graphic tablet: standard values in controls and validity in Multiple Sclerosis patients.

Aim of our study was to find a specific measure for the intensity of upper limb tremor and other ataxic symptoms in Multiple Sclerosis (MS) patients, and to establish standard values and test quality parameters. Three hundred and forty-two consecutive patients with different symptoms in the upper limbs (upper motor neuron symptoms, cerebellar upper limb ataxia, and/or sensory deficits in the upper limbs) and 140 healthy controls took part in the study. All patients and controls had to trace over a 25 cm high figure '8' on a graphic tablet, to tap with the stylus on the tablet and to perform the nine-hole-peg test (9HPT). Patients were additionally examined using clinical standard scales to classify motor dysfunctions of the upper limbs. One hundred and eighty-nine patients and 27 controls were tested twice to investigate the test reliability. Kinematic analysis of the tablet data was performed by kernel estimators, oscillatory activity by spectral analysis. Total power in the 2--10 Hz band was very specific for ataxia versus other motor symptoms. Tapping and 9HPT could well distinguish patients from controls, and patients with predominant motor neuron or cerebellar symptoms from patients with predominant sensory dysfunctions. Mean drawing error did not differ between motor and sensory dysfunctions. The test--retest reliability was similarly high for both spectral analysis and 9HPT.

Adult↗

PubMed2001

AMPA receptor activation leads to neurite retraction in tangentially migrating neurons in the intermediate zone of the embryonic rat neocortex.

In rat (König et al. [1998] 28th Annual Meeting of the Society of Neuroscience, Los Angeles. 24:314.6) and mouse (Métin et al. [2000] J. Neurosci. 20:696-708), neurons migrating tangentially in the intermediate zone (IZ) of the neocortical anlage express functional AMPA receptors permeable to calcium. The role of these receptors is as yet unknown. We exposed organotypic cultures of rat telencephalon (embryonic day 15) to AMPA receptor agonists or antagonists, and analyzed the effects of these treatments on cells in the IZ labeled with antibodies against the isoforms a, b and c of microtubule associated protein 2 (MAP2) and the polysialylated neural cell adhesion molecule (PSA-NCAM). The presence of functional AMPA receptors permeable to calcium was checked by cobalt-loading. After exposure to AMPA alone for at least 6 hr, we observed a significant increase in the number of rounded, MAP2 positive cells in the IZ close to the migratory front. When AMPA was combined with cyclothiazide, the increase was already significant after 3 hr. These effects were dose-dependent and could be partially or totally blocked by DNQX or GYKI 53655 respectively, that suggests that they are mediated by AMPA receptors. Paracrine AMPA receptor activation might participate, together with other signals, in guiding the migratory stream, or provide stop signals for migrating cells.

Animals↗

PubMed2001

[Interferon beta-1b (Betaferon)therapy in patients with relapsing-remitting multiple sclerosis: findings of a prospective, multi-center study of disease progression].

In a survey of disease course, the efficacy and tolerability of 24-month interferon beta-1b therapy for relapsing remitting multiple sclerosis (RRMS) were evaluated in 410 patients. The investigation aimed at obtaining data from general practice and of possibly unknown, unexpected adverse reactions. In the 241 patients still on therapy, efficacy was rated after 24 months as "good" or "very good" in 75% of cases. After 24 months, 36.9% of the patients had no exacerbation (baseline 0.3%). Annual exacerbation rates dropped from 1.5 before treatment to 0.7 in the second treatment year. In the 2 years before treatment, 66.2% had worsened by at least 0.5 points on the extended disability status scale (EDSS). This proportion was reduced to 41.2% after 2 years of treatment. The safety profile corresponded to results from controlled trials. This postmarketing survey supports data from the published controlled interferon beta-1b studies and confirms the main effects of this therapy under routine conditions in general practice.

Adjuvants, Immunologic↗

PubMed2001

Blockade of AMPA/kainate receptors can either decrease or increase the survival of cultured neocortical cells depending on the stage of maturation.

Neurotoxicity has often been associated with glutamate receptor stimulation and neuroprotection with glutamate receptor blockade. However, the relationship may be much more complex. We dissociated cells from the rat neocortical anlage at an early stage of prenatal development (embryonic day 14). The cells were exposed in vitro to agonists and antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainate and N-methyl-D-aspartate (NMDA) receptors and the effects on differentiation and survival have been quantitatively and qualitatively evaluated. NMDA and the non-competitive antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate (MK-801) had the expected effects (the agonist decreasing and the antagonist increasing neuronal survival) when applied at a relatively advanced stage of in vitro maturation, but no significant effect in either direction at earlier stages. Kainate also had an effect on cell survival only at an advanced stage (where it decreased the number of cells). However, this cannot be attributed to the absence of functional AMPA/kainate receptors at earlier stages, since: (1) cells could be loaded with cobalt; and (2) early application of kainate dramatically reduced the number of cobalt-positive cells. Furthermore, exposure at early stages to 6,7-dinitroquinoxaline-2,3-dione (DNQX), or GYKI 53655, (competitive and non-competitive AMPA receptor antagonists, respectively) strongly reduced cell survival. The effects were concentration- and time-dependent with a complex time--curve. The decrease in cell number was maximal after antagonist application from 2 to 5 days in vitro. The effects of DNQX could be cancelled by co-application of kainate. When exposed to an antagonist at later stages of development, the number of surviving cells gradually approached control values and finally became significantly higher. Our results suggest that cells of the developing neocortex (and perhaps newly generated cells in the adult brain) require at different stages of their development, an appropriate level of AMPA/kainate receptor activation.

Animals↗

PubMed2001

Day-to-day variability of maximum walking distance in MS patients can mislead to relevant changes in the Expanded Disability Status Scale (EDSS): average walking speed is a more constant parameter.

In this preliminary study we measured maximum walking distance and walking time on four consecutive days in 29 patients with clinically stable multiple sclerosis (MS). Patients were included in the study if they could achieve a maximum unaided walking distance of 100 up to 500 m. Our results showed a certain day-to-day variability of maximum walking distance, in some cases meaning changes up to 1.5 points in the expanded disability status scale (EDSS), which could be misinterpreted as a progression of the disease. Simultaneous measurements of maximum walking time showed a similar variability, unlike the mean walking speed which turned out to be more stable. Our results therefore suggest that scoring of MS patients should not be based on one single measurement of the maximum walking distance. The more reliable parameter appears to be the mean walking speed.

Adult↗

PubMed2001

Synaptic and non-synaptic AMPA receptors permeable to calcium.

For a long time, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors permeable to calcium have been considered to be either non-existent or as "atypical". There is now ample evidence that these receptors exist in numerous regions of the nervous system and in many neuronal as well as non-neuronal cell populations. This evidence has been accumulated by several methods, including electrophysiological recording, calcium imaging and cobalt-loading. Functional AMPA receptors permeable to calcium are already expressed at very early stages of embryonic development, well before the onset of synaptogenesis. They are probably involved in the paracrine signaling necessary for construction of the nervous system before becoming involved in synaptic transmission. In immature cells, cyclothiazide strongly increases the steady-state level of responses not only to AMPA, but also to kainate. Ingestion, during pregnancy, of food or drug substances that can cross the placental barrier and act upon the embryonic receptors may constitute a risk for normal development. In the adult nervous system, synaptic as well as non-synaptic (paracrine) AMPA receptors permeable to calcium are probably widely expressed in both glial and neuronal cells. They may also participate in controlling some aspects related to adult neurogenesis, in particular the migration of newly formed neurons.

Animals↗

PubMed2000

Intracellular distribution of mammalian protein kinase A catalytic subunit altered by conserved Asn2 deamidation.

The catalytic (C) subunit of protein kinase A functions both in the cytoplasm and the nucleus. A major charge variant representing about one third of the enzyme in striated muscle results from deamidation in vivo of the Asn2 residue at the conserved NH(2)-terminal sequence myrGly-Asn-Ala (Jedrzejewski, P.T., A. Girod, A. Tholey, N. König, S. Thullner, V. Kinzel, and D. Bossemeyer. 1998. Protein Sci. 7:457-469). Because of the increase of electronegativity by generation of Asp2, it is reminiscent of a myristoyl-electrostatic switch. To compare the intracellular distribution of the enzymes, both forms of porcine or bovine heart enzyme were microinjected into the cytoplasm of mouse NIH 3T3 cells after conjugation with fluorescein, rhodamine, or in unlabeled form. The nuclear/cytoplasmic fluorescence ratio (N/C) was analyzed in the presence of cAMP (in the case of unlabeled enzyme by antibodies). Under all circumstances, the N/C ratio obtained with the encoded Asn2 form was significantly higher than that with the deamidated, Asp2 form; i.e., the Asn2 form reached a larger nuclear concentration than the Asp2 form. Comparable data were obtained with a human cell line. The differential intracellular distribution of both enzyme forms is also reflected by functional data. It correlates with the degree of phosphorylation of the key serine in CREB family transcription factors in the nucleus. Microinjection of myristoylated recombinant bovine Calpha and the Asn2 deletion mutant of it yielded N/C ratios in the same range as encoded native enzymes. Thus, Asn2 seems to serve as a potential site for modulating electronegativity. The data indicate that the NH(2)-terminal domain of the PKA C-subunit contributes to the intracellular distribution of free enzyme, which can be altered by site-specific in vivo deamidation. The model character for other signaling proteins starting with myrGly-Asn is discussed.

Amides↗

PubMed2000

The amino terminus of PKA catalytic subunit--a site for introduction of posttranslational heterogeneities by deamidation: D-Asp2 and D-isoAsp2 containing isozymes.

Conserved deamidation of PKA catalytic subunit isozymes Calpha and Cbeta--more than 25% at Asn2 in vivo in both cases--has been shown to yield Asp2- and isoAsp2-containing isozymes (Jedrzejewski PT, Girod A, Tholey A, König N, Thullner S, Kinzel V, Bossemeyer D, 1998, Protein Sci 7:457-469). Isoaspartate formation in proteins in vivo is indicative of succinimide intermediates involved in both the initial deamidation reaction as well as the "repair" of isoAsp to Asp by the action of protein L-isoaspartyl (D-aspartyl) O-methyl transferase (PIMT). L-Succinimide is prone to racemization to D-succinimide, which may hydrolyze to D-isoAsp- and D-Asp-containing diastereomers with, respectively, no and poor substrate character for PIMT. To analyze native PKA catalytic subunit from cardiac muscle for these isomers the N-terminal tryptic peptides (T1) of the enzyme were analyzed following procedures refined specifically with a set of corresponding synthetic peptides. The methods combined high resolution high-performance liquid chromatography and a new mass spectrometric procedure for the discrimination between Asp- and isoAsp-residues in peptides (Lehmann et al., 2000). The results demonstrate the occurrence of D-isoAsp- and D-Asp-containing T1 fragments in addition to the L-isomers. The small amount of the L-isoAsp isomer, representing only part of the D-isoAsp isomer, and the relatively large amounts of the L-Asp and D-Asp isomers argues for an effective action of PIMT present in cardiac tissue.

Animals↗

PubMed1999

CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis.

Interleukin-6 (IL-6) has recently been implicated in multiple sclerosis (MS), since IL-6 deficient mice were resistant to a demyelinating form of experimental autoimmune encephalomyelitis and IL-6 expression was upregulated in MS. The cytokine IL-6 and its action mediating soluble receptors (sIL-6R and sgp130) were measured in cerebrospinal fluid (CSF) and serum of 61 MS patients and 39 controls. In the presence of unchanged IL-6 concentrations, sIL-6R and sgp130 serum levels were significantly increased in MS and correlated with disease severity. Furthermore, sgp130 CSF levels were decreased in MS, suggesting a possibly altered IL-6 regulation in the CSF.

Adult↗

PubMed1999

Embryonic raphe neurons grafted in vitro on fetal spinal cord slices recognize specific target areas.

To investigate the characteristics of neurotropic signaling involved in specific target recognition by grafted embryonic serotonergic cells, we have developed an in vitro grafting model. Specific raphe nuclei (B1/B2 and B3) were respectively dissected from 14-day-old rat embryos, and partially dissociated cells were cocultured on spinal cord slices from 20-day-old fetuses. After serotonin immunodetection, neurite growth patterns were analyzed by standard photonic or confocal scanning microscopy. Computer reconstruction (maximal signal projection) was used to track individual neurites in spite of their changing depth levels. Whereas the direction and branching of the initial neurite segments did not seem to be significantly influenced by any specific environment, specific growth patterns were developed at some distance from the cell bodies, indicating that neurites are able to recognize their specific targets.

Animals↗

PubMed1999

AMPA/kainate receptors permeable to divalent cations in amphibian central nervous system.

Glutamate receptors have been studied extensively in mammals but less explored in lower vertebrates. These receptors are present in amphibians. Using a recent method based upon agonist-induced cobalt uptake, we were able to detect the presence of functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors permeable to divalent cations in tadpoles and in adults. The uptake specificity was checked by co-application of an antagonist. We studied the distribution of receptor-bearing cells in the principal brain regions. The distribution was similar in the two species studied: Rana esculenta (green frog) and Bufo bufo (common toad). The high number of cobalt-positive cells suggests that the AMPA/kainate receptors permeable to divalent cations play an important role in the anuran nervous system.

Animals↗

PubMed1998

A conserved deamidation site at Asn 2 in the catalytic subunit of mammalian cAMP-dependent protein kinase detected by capillary LC-MS and tandem mass spectrometry.

The N-terminal sequence myr-Gly-Asn is conserved among the myristoylated cAPK (protein kinase A) catalytic subunit isozymes Calpha, Cbeta, and Cgamma. By capillary LC-MS and tandem MS, we show that, in approximately one third of the Calpha and Cbeta enzyme populations from cattle, pig, rabbit, and rat striated muscle, Asn 2 is deamidated to Asp 2. This deamidation accounts for the major isoelectric variants of the cAPK C-subunits formerly called CA and CB. Deamidation also includes characteristic isoaspartate isomeric peptides from Calpha and Cbeta. Asn 2 deamidation does not occur during C-subunit preparation and is absent in recombinant myristoylated Calpha (rCalpha) from Escherichia coli. Deamidation appears to be the exclusive pathway for introduction of an acidic residue adjacent to the myristoylated N-terminal glycine, verified by the myristoylation negative phenotype of an rCalpha(Asn 2 Asp) mutant. This is the first report thus far of a naturally occurring myr-Gly-Asp sequence. Asp 2 seems to be required for the well-characterized (auto)phosphorylation of the native enzyme at Ser 10. Our results suggest that the myristoylated N terminus of cAPK is a conserved site for deamidation in vivo. Comparable myr-Gly-Asn sequences are found in several signaling proteins. This may be especially significant in view of the recent knowledge that negative charges close to myristic acid in some proteins contribute to regulating their cellular localization.

Amides↗

PubMed1998

[Local ice application in therapy of kinetic limb ataxia. Clinical assessment of positive treatment effects in patients with multiple sclerosis].

Upper limb ataxia is one of the most disabling symptoms of patients with multiple sclerosis (MS). There are some clinically tested therapeutic strategies, especially with regard to cerebellar tremor. But most of the methods used for treatment of limb ataxia in physiotherapy and occupational therapy are not systematically evaluated, e.g. the effect of local ice applications, as reported by MS patients and therapists, respectively. We investigated 21 MS patients before and in several steps 1 up to 45 min after cooling the most affected forearm. We used a series of 6 tests, including parts of neurological status and activities of daily living as well. At each step skin temperature and nerve conduction velocity were recorded. All tests were documented by video for later offline analysis. Standardized evaluation was done by the investigators and separately by an independent second team, both of them using numeric scales for quality of performance. After local cooling all patients showed a positive effect, especially a reduction of intentional tremor. In most cases this effect lasted 45 min, in some patients even longer. We presume that a decrease in the proprioceptive afferent inflow-induced by cooling-may be the probable cause of this reduction of cerebellar tremor. Patients can use ice applications as a method of treating themselves when a short-time reduction of intention tremor is required, e.g. for typing, signing or self-catheterization.

Activities of Daily Living↗

PubMed1998

Functional AMPA/kainate receptors in human embryonic and foetal central nervous system.

Here, functional AMPA/kainate receptors in human embryonic (5.5-7.5 gestational weeks) and foetal (8-10 gestational weeks) central nervous system tissue, shown by the cobalt labeling method, are reported. Specific agonist-induced cobalt incorporation was detected in brainstem and spinal cord cells, even in the youngest embryo studied. T-AMPA or kainate, but also vegetal toxins such as L-BOAA or acromelate, induced accumulation of cobalt. In contrast, no labeling was observed after exposure to KCl or NMDA. Cobalt labeled cells were particularly prominent in motor regions of brainstem and spinal cord. Co-application of the diuretic agent cyclothiazide, a desensitization blocker at AMPA receptors, dramatically increased the number of stained cells, which was particularly obvious in sensory regions, suggesting different receptor properties in motor versus sensory regions. This is the first study providing evidence for functional AMPA/kainate receptors, permeable to divalent cations, in brainstem and spinal cord at an early stage of human central nervous system development. Since many developmental processes are influenced by the modulation of cytosolic calcium, exposure at critical stages of embryogenesis to food or drug substances modifying the activity of AMPA/kainate receptors may alter brain development.

Amino Acids, Diamino↗

PubMed1998

Quality of life in multiple sclerosis in France, Germany, and the United Kingdom. Cost of Multiple Sclerosis Study Group.

OBJECTIVE: To assess the quality of life (QoL) of patients with multiple sclerosis in France, Germany, and the United Kingdom with a cross sectional study. METHODS: Patients were classified into three severity groups according to the expanded disability severity scale (EDSS); stage I, II, and III, corresponding to mild (EDSS 1.0-3.5), moderate (EDSS 4.0-6.0), or severe (EDSS 6.5-8.0) multiple sclerosis respectively. Ninety patients with multiple sclerosis and 30 control patients without multiple sclerosis were recruited in each country. Control patients were matched to the patients with multiple sclerosis according to age and sex. Quality of life was assessed using the functional status questionnaire (FSQ). RESULTS: The aspects of QoL that were mostly affected in the three countries under study were physical function and general wellbeing. Social role function decreased with increased severity of disease in France and in particular in Germany. Multiple sclerosis did not seem to have an impact on psychological function. The QoL of control patients was systematically higher than that of patients with multiple sclerosis. CONCLUSIONS: Use of such a generic scale showed that progression of multiple sclerosis is accompanied by a decrease in QoL and suggested that this could be a relevant measurement in assessing the effect of treatment and progression of disease. Variation between countries, however, may be important.

Adult↗

PubMed1998

Economic evaluation of multiple sclerosis in the UK, Germany and France.

A cross-sectional cost-of-care study was performed to assess the economic burden of multiple sclerosis (MS) in France, Germany and the UK. Patients were stratified into 3 groups according to the Expanded Disability Severity Scale (EDSS): stages I, II and III, corresponding to mild (EDSS 1.0 to 3.5), moderate (EDSS 4.0 to 6.0) and severe (EDSS 6.5 to 8.0) MS, respectively. 90 patients with MS and 30 non-MS control patients were recruited in each country. Control patients were matched to the patients with MS on the basis of age and gender. Demographic, clinical and economic data during the 3-month period prior to entry were collected in patient interviews. Total costs included actual expenditures, such as direct medical and non-medical costs, as well as indirect costs. From the societal perspective, the total cost of MS for 3 months was estimated at 1,928 US dollars, 3,941 US dollars and 5,678 US dollars in France, 2,772 US dollars, 2,056 dollars and 5701dollars in Germany, and 5,125 US dollars, 6,751 US dollars and 14, 622 US dollars in the UK, for stage I, II and III patients, respectively. The major medical cost driver in the UK was outpatient consultations, whereas hospitalisations were the major component in Germany and France. The major cost in the UK arose from the dependence of patients with MS on caregivers, which caused high non-medical, societal costs compared with France and Germany. From both the societal and health insurance perspectives in each country, costs for control patients were lower than those for stage I MS patients. MS represents a major financial burden on the individual, the family, health services and society, and these costs increase with MS progression.

Adult↗