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Biomedical subjects

M Naumann

Publications and source records attributed to M Naumann.

At least 55 records · Page 3Linked to original sources
PubMed2001

Modulation of growth factor binding properties of alpha2-macroglobulin by enzyme therapy.

PURPOSE: To investigate the binding of transforming growth factor-beta (TGF-beta) to human alpha2-macroglobulin upon oral treatment of patients with proteases. METHODS: Volunteers were given a cocktail of active proteinases (Phlogenzym) composed of trypsin, bromelain and the additive rutoside orally over a period of 7 days at low dose followed by a bolus application. Before and after medication plasma was immediately withdrawn and binding of 125I-TGF-beta to the proteinase inhibitor alpha2-macroglobulin was determined by electrophoresis and gamma-counting. Cell culture experiments were performed to study the effect of transformed alpha2-macroglobulin on TGF-beta-stimulated proliferation of skin fibroblasts. RESULTS: Ingestion of proteinases was found to trigger the formation of intermediate forms of alpha2-macroglobulin displaying high affinity to TGF-beta. Maximum binding of TGF-beta was observed 1-2 h after bolus ingestion, and steadily levelled off with time. In vitro experiments demonstrated that complex formation of diverse proteinases (trypsin, alpha-chymotrypsin, bromelain and plasmin) with alpha2-macroglobulin conferred binding of 125I-TGF-beta, alpha2-Macroglobulin transformed by methylamine or proteinases was found to abolish the TGF-beta effect on fibroblasts in cell culture. CONCLUSIONS: Intestinal absorption of proteinases triggers the formation of TGF-beta binding species of alpha2-macroglobulin in blood. Mediated by this process high concentrations of TGF-beta might be reduced via enhanced clearance of alpha2-macroglobulin-TGF-beta complexes. Thus, proteinase therapy may have beneficial effects in treatment of fibrosis and certain cancers accompanied by excessively high TGF-beta concentrations.

Administration, Oral↗
PubMed2001

Cerebral activation patterns in patients with writer's cramp: a functional magnetic resonance imaging study.

Functional MRI (fMRI), visualizing changes in cerebral blood oxygenation, has to date not been performed either in patients with writer's cramp or in healthy subjects during writing. We compared the cerebral and cerebellar activation pattern of 12 patients with writer's cramp during writing with a group of 10 healthy subjects performing the same tasks over 30-s periods of rest or writing. Sixty echo planar imaging multislice datasets were analysed using SPM96 software. Data were analysed for each subject individually and groupwise for patients vs. controls. Healthy subjects showed a significant activation of the ipsilateral dentate nucleus, contralateral cerebellar hemisphere, contralateral primary sensorimotor cortex, and contralateral precentral gyrus during writing. Patients with writer's cramp showed significantly greater activation of the ipsilateral cerebellar hemisphere than controls. Also the activation in the primary sensorimotor cortex extended further caudally and anteriorly towards the premotor association area. Activation was observed in the thalamus during writing only among the patients. Our results indicate an increased basal ganglia output via the thalamus to the motor and premotor cortical areas in dystonia patients and support the notion of disinhibition of the motor cortex leading to cocontractions and dystonic postures.

Adult↗
PubMed2001

Morphine in tardive and idiopathic dystonia (short communication).

Opioids have been shown to improve L-Dopa induced dyskinesias in patients with Parkinson's disease. In this pilot trial of five patients with tardive and four patients with idiopathic dystonia we tested the effect of morphinsulfate in a retarded form with a dosage of 20-60 mg per day. A substantial improvement of dystonic movements could be observed in four patients with tardive and one patient with idiopathic dystonia. The effect was only transient in tardive dystonia while pain relief mediated by morphine overlasted the effect on involuntary movements.

Adult↗
PubMed2001

Quality of life in patients with blepharospasm.

OBJECTIVES: Administration of botulinum neurotoxin A (BONT/A) is a common and effective treatment of blepharospasm. There is, however, no information regarding the emotional and social well-being of patients with blepharospasm and patient acceptance of BONT/A therapy. The purpose of this study was to investigate aspects of quality of life of patients with blepharospasm and level of patient satisfaction with treatment. MATERIAL AND METHODS: Fifty-one patients with blepharospasm who had been treated with BONT/A for years completed a questionnaire providing information about quality of life. RESULTS: Results revealed reductions in social and emotional well-being of patients but, nonetheless, good acceptance of BONT/A therapy. The positive effects of BONT/A therapy were, however, accompanied by fear of a decreasing effect of BONT/A injections. CONCLUSION: Although the objective findings following BONT/A injections in the treatment of blepharospasm are appreciated by the patients, their well-being is affected by fears and depression.

Aged↗
PubMed2001

Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.

Adolescent↗
PubMed2001

Pathogenicity island-dependent activation of Rho GTPases Rac1 and Cdc42 in Helicobacter pylori infection.

Helicobacter pylori has been identified as the major aetiological agent in the development of chronic gastritis and duodenal ulcer, and it plays a role in the development of gastric carcinoma. Attachment of H. pylori to gastric epithelial cells leads to nuclear and cytoskeletal responses in host cells. Here, we show that Rho GTPases Rac1 and Cdc42 were activated during infection of gastric epithelial cells with either the wild-type H. pylori or the mutant strain cagA. In contrast, no activation of Rho GTPases was observed when H. pylori mutant strains (virB7 and PAI) were used that lack functional type IV secretion apparatus. We demonstrated that H. pylori-induced activation of Rac1 and Cdc42 led to the activation of p21-activated kinase 1 (PAK1) mediating nuclear responses, whereas the mutant strain PAI had no effect on PAK1 activity. Activation of Rac1, Cdc42 and PAK1 represented a very early event in colonization of gastric epithelial cells by H. pylori. Rac1 and Cdc42 were recruited to the sites of bacterial attachment and are therefore probably involved in the regulation of local and overall cytoskeleton rearrangement in host cells. Finally, actin rearrangement and epithelial cell motility in H. pylori infection depended on the presence of a functional type IV secretion system encoded by the cag pathogenicity island (PAI).

Antigens, Bacterial↗
PubMed2001

Cognitive response control in writer's cramp.

Disturbances of the motor and sensory system as well as an alteration of the preparation of movements have been reported to play a role in the pathogenesis of dystonias. However, it is unclear whether higher aspects of cortical - like cognitive - functions are also involved. Recently, the NoGo-anteriorization (NGA) elicited with a visual continuous performance test (CPT) during recording of a 21-channel electroencephalogram has been proposed as an electrophysiological standard-index for cognitive response control. The NGA consists of a more anterior location of the positive area of the brain electrical field associated with the inhibition (NoGo-condition) compared with that of the execution (Go-condition) of a prepared motor response in the CPT. This response control paradigm was applied in 16 patients with writer's cramp (WC) and 14 age matched healthy controls. Topographical analysis of the associated event-related potentials revealed a significant (P < 0.05) NGA effect for both patients and controls. Moreover, patients with WC showed a significantly higher global field power value (P < 0.05) in the Go-condition and a significantly higher difference-amplitude (P < 0.05) in the NoGo-condition. A source location analysis with the low resolution electromagnetic tomography (LORETA) method demonstrated a hypoactivity for the Go-condition in the parietal cortex of the right hemisphere and a hyperactivity in the NoGo-condition in the left parietal cortex in patients with WC compared with healthy controls. These results indicate an altered response control in patients with WC in widespread cortical brain areas and therefore support the hypothesis that the pathogenesis of WC is not restricted to a pure sensory-motor dysfunction.

Adult↗
PubMed2001

Host cell signaling in Helicobacter pylori infection.

Helicobacter pylori represents a highly successful human microbial pathogen that has infected approximately half of the world's population. This gram-negative microorganism colonizes the human epithelial layer in the stomach and induces a state of chronic inflammation that does not resolve the underlying infection and often leads to gastric or duodenal ulcers, or more rarely to gastric cancer. Among the reactions in H. pylori-infected epithelial cells the induction of proinflammatory cytokines, cell spreading and movement, as well as a scattered phenotype appear strictly dependent on the expression of pathogenicity island-encoded proteins in H. pylori. This review will discuss the features of the H. pylori-induced signal transduction leading to changes in host cellular function. Topics discussed comprise the signaling and the phenotypes associated with the type IV secretion system, the activation of target genes involved in gastric physiology, and putative mechanisms leading to the development of gastric cancer.

Epithelial Cells↗
PubMed2001

Reduction of Menkes mRNA and copper in leukocytes of patients with primary adult-onset dystonia.

Studies on postmortem tissue of patients with primary adult-onset dystonia revealed a significant increase in copper levels and a reduction of copper transporting Menkes protein of the lentiform nuclei. Here we demonstrate that patients with idiopathic adult-onset cervical dystonia (n = 14) have reduced Menkes mRNA copies and lower copper levels in leukocytes compared to controls (n = 17; U test, p < 0.05). Changes were less distinct in patients with blepharospasm. Therefore, disturbances of copper metabolism in focal dystonia may not be restricted to the basal ganglia.

Adenosine Triphosphatases↗
PubMed2000

p21-activated kinase 1 activates the nuclear factor kappa B (NF-kappa B)-inducing kinase-Ikappa B kinases NF-kappa B pathway and proinflammatory cytokines in Helicobacter pylori infection.

Helicobacter pylori, the causative agent of several human gastric diseases, induces activation of the immediate early response transcription factor nuclear factor kappaB (NF-kappaB), which subsequently triggers release of proinflammatory cytokines in colonized epithelial cells. Here we report that in H. pylori infection p21-activated kinase 1 (PAK1) activates NF-kappaB. Activated PAK1 associates with NF-kappaB-inducing kinase, which upon activation directs the activity of IkappaB kinases to IkappaBalpha. Our results indicate that in epithelial cells PAK1 participates in a unique pathway that links H. pylori-dependent effector molecules to the activation of NF-kappaB and the induction of the innate immune response.

Cell Line↗
PubMed2000

Nuclear factor-kappa B activation and innate immune response in microbial pathogen infection.

Human pathogenic microorganisms have developed a variety of strategies to infect the host organism successfully, whereas the host has evolved a series of defense mechanisms. In most cases, the epithelial cell layer represents the first barrier for the bacterial pathogen and triggers the innate and inflammatory responses in the host. Epithelial cells release proinflammatory mediators including cytokines and chemokines, leading to the subsequent attraction of monocytes/macrophages. Therefore, epithelial cells represent an immediate-early warning system in the host organism. Subsequent to the colonization of the epithelial layer, invasive microbial pathogens often induce an acute inflammatory response, which functions to activate residential macrophages and recruits blood leukocytes to the site of infection. Distinct receptors of the Toll family on the cell surface of immune cells mediate antibacterial responses in mammals as well as in Drosophila. One of the most important cellular factors involved in the regulation of the host innate antimicrobial response is the immediate-early response transcription factor nuclear factor (NF)-kappa B. Microbial pathogens activate cellular signal transduction pathways that induce NF-kappa B activation, but pathogens also find ways to overcome the innate immune response through active manipulation of the NF-kappa B signal transduction pathways. Exploration of the mechanisms that influence NF-kappa B activity could contribute to a better understanding of the molecular pathogenesis of microbial infections and could be important for potential therapeutic intervention that may be relevant in a wide variety of inflammatory diseases.

Animals↗
PubMed2000

Helicobacter pylori activates the histidine decarboxylase promoter through a mitogen-activated protein kinase pathway independent of pathogenicity island-encoded virulence factors.

Helicobacter pylori infection of the gastric mucosa is accompanied by an activated histamine metabolism. Histamine plays a central role in the regulation of gastric acid secretion and is involved in the pathogenesis of gastroduodenal ulcerations. Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production, and its activity is regulated through transcriptional mechanisms. The present study investigated the effect of H. pylori infection on the transcriptional activity of the human HDC (hHDC) promoter in a gastric epithelial cell line (AGS) and analyzed the underlying molecular mechanisms. Our studies demonstrate that H. pylori infection potently transactivated the hHDC promoter. The H. pylori-responsive element of the hHDC gene was mapped to the sequence +1 to +27 base pairs, which shows no homology to known cis-acting elements and also functions as a gastrin-responsive element. H. pylori regulates the activity of this element via a Raf-1/MEK/ERK pathway, which was activated in a Ras-independent manner. Furthermore, we found that H. pylori-induced transactivation of the hHDC promoter was independent of the cag pathogenicity island and the vacuolating cytotoxin A gene and therefore may be exerted through (a) new virulence factor(s). A better understanding of H. pylori-directed hHDC transcription can provide novel insights into the molecular mechanisms of H. pylori-dependent gene regulation in gastric epithelial cells and may lead to new therapeutic approaches.

Helicobacter pylori↗
PubMed2000

Purification, molecular and kinetic characterization of phosphofructokinase-1 from the yeast Schizosaccharomyces pombe: evidence for an unusual subunit composition.

Phosphofructokinase-1 (Pfk-1) from Schizosaccharomyces pombe was purified by 54-fold enrichment to homogeneity elaborating the following steps: (a) Disruption of the cells with glass beads; (b) fractionated precipitation with polyethylene glycol 6000; (c) affinity chromatography on Cibacron-Blue F3G-A-Sephadex G 100; (d) ion exchange chromatography on Resource Q. The native enzyme exhibits a mass of 790+/-30 kDa, as detected by sedimentation equilibrium measurements. The apparent sedimentation coefficient was found to be s(20,c)=20.2+/-0.3 S. No significant dependence of the s-value on the protein concentration was observed in the range 0. 07-0.7 mg/ml. Polyacrylamide gel electrophoresis in presence of sodium dodecyl sulphate and MALDI-TOF spectra showed that the enzyme is composed of subunits of identical size of 100+/-5 kDa, forming an octameric structure. The N-terminus of the enzyme was found to be blocked. Sequences of tryptic and chymotryptic peptides of the subunit coincide with the proposed amino acid sequence as deduced from the gene from the EMBL library. The Pfk-1 coding sequence of S. pombe was transformed into a Pfk-1 double deletion mutants of Saccharomyces cerevisiae resulting in glucose-positive cells with enzyme activity in the crude cell extract. The kinetic analysis revealed less cooperativity to fructose 6-phosphate (n(H)=1.6) and less inhibition by ATP as compared to the enzyme from baker's yeast. Fructose 2,6-bisphosphate (in micromolar range) and AMP (in millimolar range) were found to overcome ATP inhibition and to increase the affinity to fructose 6-phosphate.

Adenosine Monophosphate↗
PubMed2000

The DYT1 GAG deletion is infrequent in sporadic and familial writer' s cramp.

A 3-base pair (GAG) deletion in the DYT1 gene has recently been found to be responsible for most cases of early-onset primary generalized dystonia. In some cases, this mutation has been associated with writer's cramp. To determine the frequency of this mutation in a larger series of patients, we examined 44 index patients with sporadic or familial (seven patients) writer's cramp for the presence of the DYT1 GAG deletion, including eight patients with segmental dystonia involving at least one upper limb. We found the mutation in none of these index patients, which confirms that isolated writer's cramp is only in rare cases a phenotypic manifestation of this mutation, even if a positive family history of writer's cramp is present.

Adult↗
PubMed2000

Management of spasticity associated pain with botulinum toxin A.

Lesions of the central nervous system often result in an upper motor neuron syndrome including spasticity, paresis with pyramidal signs, and painful spasms. Pharmacological treatment with oral antispasticity drugs is frequently associated with systemic side effects which limit their clinical use. Botulinum Toxin A (BtxA) injected in spastic muscles has been shown to be effective in reducing muscle tone, but only few studies have reported pain relief as additional benefit. Therefore, we investigated the effects of local BtxA injections in 60 patients with acute (< 12 months) and chronic spasticity and pain in a prospective multicenter study. Target muscles for BtxA were selected on the basis of clinical examination. Intramuscular BtxA injections were placed in muscles exhibiting increased muscle tone in combination with pain during passive joint movement. Patients received a mean total dose of 165.7 +/- 108.2 [30-400] units BOTOX((R)) per treatment session in a mean 3.4 +/- 1.5 muscles. Baseline and follow-up (mean 5.9 weeks) measures included a patient self-assessment of pain and function on a five-level scale, a physician's evaluation of function, and a global rating of response to BtxA. Fifty-four of sixty patients experienced improvement in pain without subjective functional improvement. The effects were comparable in acute (n = 17) and chronic (n = 43) spasticity. Physician's assessment of gain in function increased significantly (p < 0.05) only in patients with chronic spasticity. No serious adverse event was observed. Mild reversible side effects (local pain, hematoma, edema, mild weakness) were observed in four patients. In conclusion, we found that intramuscular BtxA injections are a potent, well-tolerated treatment modality to significantly reduce spasticity-related local pain. This problem may be a main indication, especially in patients with poor response or intolerable side effects to oral medication.

Adolescent↗
PubMed2000

Effective treatment of frontal hyperhidrosis with botulinum toxin A.

BACKGROUND: Focal hyperhidrosis is a common condition mostly confined to the axillae, palms and soles. In some individuals, predominantly men, increased sweating of the forehead may be the major complaint and may interfere with the person's quality of life. Botulinum toxin A has been shown to be a very effective treatment for focal hyperhidrosis of the axillae and palms. OBJECTIVES: To assess the response in 10 men suffering from frontal hyperhidrosis treated with botulinum toxin A. METHODS: Botulinum toxin A Botox was injected at multiple sites evenly distributed over the forehead (mean dose 86 mouse units). RESULTS: The mean +/- SEM amount of sweat was significantly reduced, 4 weeks after treatment, from 173.8 +/- 38.6 mg min(-1) to 53.7 +/- 17.6 mg min(-1). The effect lasted at least 5 months in nine of the 10 patients. All patients subjectively judged the treatment as very effective. Minor side-effects included painful injections and a transient weakness of forehead muscles without ptosis. CONCLUSIONS: In this study, we provide evidence that botulinum toxin A is an effective and safe treatment for frontal hyperhidrosis.

Adult↗