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Biomedical subjects

M Krause

Publications and source records attributed to M Krause.

At least 73 records · Page 4Linked to original sources
PubMed2001

Deep brain stimulation for the treatment of Parkinson's disease: subthalamic nucleus versus globus pallidus internus.

OBJECTIVES: Deep brain stimulation of the basal ganglia has become a promising treatment option for patients with Parkinson's disease who have side effects from drugs. Which is the best target-globus pallidus internus (GPi) or subthalamic nucleus (STN)-is still a matter of discussion. The aim of this prospective study is to compare the long term effects of GPi and STN stimulation in patients with severe Parkinson's disease. PATIENTS AND METHODS: Bilateral deep brain stimulators were implanted in the GPi in six patients and in the STN in 12 patients with severe Parkinson's disease. Presurgery and 3, 6, and 12 months postsurgery patients were scored according to the CAPIT protocol. RESULTS: Stimulation of the STN increased best Schwab and England scale score significantly from 62 before surgery to 81 at 12 months after surgery; GPi stimulation did not have an effect on the Schwab and England scale. Stimulation of the GPi reduced dyskinesias directly whereas STN stimulation seemed to reduce dyskinesias by a reduction of medication. Whereas STN stimulation increased the unified Parkinson's disease rating scale (UPDRS) motor score, GPi stimulation did not have a significant effect. Fluctuations were reduced only by STN stimulation and STN stimulation suppressed tremor very effectively. CONCLUSION: Stimulation of the GPi reduces medication side effects, which leads to a better drug tolerance. There was no direct improvement of bradykinesia or tremor by GPi stimulation. Stimulation of the STN ameliorated all parkinsonian symptoms. Daily drug intake was reduced by STN stimulation. The STN is the target of choice for treating patients with severe Parkinson's disease who have side effects from drugs.

Aged↗
PubMed2001

Hemangiosarcoma of the bone. Problems arising from the heterogeneity of malignant vascular tumors of the bone.

BACKGROUND: Hemangioendothelioma of the bone is a rare vasoformative tumor of the bone with an intermediately aggressive nature. The tumor is said to have a long clinical course depending on the sites involved. Diagnosis is particularly difficult since vascular tumors of the bone often present heterogeneous differentiation. CASE REPORT: We report on a 65-year-old female patient who had been diagnosed with an epitheloid hemangioendothelioma of the iliac bone and who underwent wide local excision. Although the initial biopsy specimens had clearly shown an epitheloid hemangioendothelioma, the final pathological analysis revealed a heterogeneous tumor, partially with some characteristics of an epitheloid hemangiosarcoma. The patient subsequently developed pulmonary metastasis, received a multimodality treatment, but died 14 months after the initial diagnosis from pulmonary insufficiency due to pleural sarcomatosis. CONCLUSION: Hemangioendothelioma of the bone needs to be discussed as a differential diagnosis of osteolytic lesions. Our case stresses the importance of multimodality treatment in centers for cancer treatment. Histopathologic evaluation is essential in the diagnosis of epitheloid hemangioendothelioma. It is particularly difficult due to the heterogeneous differentiation of vasoformative tumors of the bone.

Aged↗
PubMed2001

Evidence for a molecular complex consisting of Fyb/SLAP, SLP-76, Nck, VASP and WASP that links the actin cytoskeleton to Fcgamma receptor signalling during phagocytosis.

Phagocytosis by macrophages and neutrophils involves the spatial and temporal reorganisation of the actin-based cytoskeleton at sites of particle ingestion. Local polymerisation of actin filaments supports the protrusion of pseudopodia that eventually engulf the particle. Here we have investigated in detail the cytoskeletal events initiated upon engagement of Fc receptors in macrophages. Ena/vasodilator-stimulated phosphoprotein (VASP) proteins were recruited to phagosomes forming around opsonised particles in both primary and immortalised macrophages. Not only did the localisation of Ena/VASP proteins coincide, spatially and temporally, with the phagocytosis-induced reorganisation of actin filaments, but their recruitment to the phagocytic cup was required for the remodelling of the actin cytoskeleton, extension of pseudopodia and efficient particle internalisation. We also report that SLP-76, Vav and profilin were recruited to forming phagosomes. Upon induction of phagocytosis, a large molecular complex, consisting in part of Ena/VASP proteins, the Fyn-binding/SLP-76-associated protein (Fyb/SLAP), Src-homology-2 (SH2)-domain-containing leukocyte protein of 76 kDa (SLP-76), Nck, and the Wiskott-Aldrich syndrome protein (WASP), was formed. Our findings suggest that activation of Fcgamma receptors triggers two signalling events during phagocytosis: one through Fyb/SLAP that leads to recruitment of VASP and profilin; and another through Nck that promotes the recruitment of WASP. These converge to regulate actin polymerisation, controlling the assembly of actin structures that are essential for the process of phagocytosis.

Actins↗
PubMed2001

Azomethine prodrugs of (R)-alpha-methylhistamine, a highly potent and selective histamine H3-receptor agonist.

The histamine H3 receptor is considered a potential target for novel drugs as it regulates the activity of various neurotransmitters in the peripheral and the central nervous system. Particularly H3-receptor agonists have been suggested to become valuable drugs for the treatment of several CNS disorders, inflammatory and acid related diseases. Due to its strong basicity and polarity the highly potent and selective histamine H3-receptor agonist (R)-alpha-methylhistamine hardly penetrates biological membranes and is furthermore rapidly inactivated in vivo. Thus, lipophilic, non-basic azomethine prodrugs of (R)-alpha--methylhistamine have been developed to overcome its pharmacokinetic disadvantages. This bioreversible derivatization decreased its basicity, increased its lipophilicity and reduced its metabolization. As a result the biological half-life was prolonged and oral absorption as well as penetration into the brain were significantly increased. By systematic variation of the pro-moiety we were able to optimize the pharmacokinetic properties which allow for both peripheral and central delivery of the parent amine. The azomethine prodrugs described herein display satisfactory stability to be orally administered while being adequately labile to deliver (R)-alpha-methylhistamine at sufficient concentrations in vivo. At present, these azomethines not only serve as valuable tools for pharmacological studies related to the histamine H3 receptor, but also represent a promising approach to achieve therapeutic application of the histamine H3-receptor agonist (R)-alpha-methylhistamine. Currently the parent compound of the prodrugs is under clinical development phase II.

Animals↗
PubMed2001

Directed biosynthesis of new enniatins.

New cyclohexadepsipeptides of the enniatin type with potential anthelmintic properties were produced by two different strategies: 1. In vitro synthesis by use of the multienzyme enniatin synthetase, and 2. in vivo precursor feeding of enniatin producing strains Fusarium scirpi and Fusarium sambucinum. The compounds were analyzed by HPLC, various NMR measurements and mass spectrometry. The three N-methyl L-amino acid positions in the enniatin B molecule could be gradually replaced by other (N-methyl) L-amino acids, e.g. alanine, cysteine, threonine and serine. The latter two amino acids yield new enniatins with functional groups in the hydrophobic side chains. Similarly the three D-2-hydroxyisovalerate residues, present in all naturally occuring enniatins, could be substituted by D-2-hydroxybutyric acid and D-lactic acid. Despite its lower yield the in vitro synthesis has the advantage of a broader variety of products formed.

Anthelmintics↗
PubMed2001

[Disseminated actinic keratoses. Comparison of topical photodynamic therapy with 5-aminolevulinic acid and topical 5% imiquimod cream].

We report on a 75-year-old woman with skin type I suffering for 20 years from multiple actinic keratoses of areas exposed to the sun. The skin of her forearms was treated on one side with imiquimod 5% cream over 4 weeks and on the contralateral side with photodynamic therapy (PDT) using topical 5-aminolevulinic acid (ALA). Both sides showed good clinical response after 3-months follow-up, suggesting that these modalities can be effectively used for treating widespread multiple actinic keratoses.

Adjuvants, Immunologic↗
PubMed2000

[Anemia and thrombocytopenia of uncertain etiology].

A 35-year-old male patient with long lasting HIV infection presented with confusion, haemolytic anaemia and thrombocytopenia. After a stable course over 7 days he suddenly developed coma and cardiogenic shock and died. Autopsy revealed thrombotic thrombocytopenic purpura with fibrin-rich deposits in the microvasculature of the brain, heart and pancreas. The pathogenesis and differential diagnosis of this fulminant disease are discussed.

Adult↗
PubMed2000

Ordered networks of rat hippocampal neurons attached to silicon oxide surfaces.

The control of neuronal cell position and outgrowth is of fundamental interest in the development of applications ranging from cellular biosensors to tissue engineering. We have produced rectangular networks of functional rat hippocampal neurons on silicon oxide surfaces. Attachment and network formation of neurons was guided by a geometrical grid pattern of the adhesion peptide PA22-2 which matches in sequence a part of the A-chain of laminin. PA22-2 was applied by contact printing onto the functionalised silicon oxide surface and was immobilised by hetero-bifunctional cross-linking with sulfo-GMBS. Geometric pattern matching was achieved by microcontact printing using a polydimethylsiloxane (PDMS) stamp. In this way the produced grid pattern ranged from 3 to 20 microm in line width and from 50 to 100 microm in line distances. As shown by atomic force microscopy (AFM), line widths and line distances of the peptide pattern differ less than 0.5 microm from the used PDMS stamp. The height of the layer of immobilised PA22-2 was approximately 3.5 nm implying the layer to be monomolecular. Immobilised PA22-2 was capable of binding anti-PA22-2 antibodies indicating that the function of the peptide was not compromised by immobilisation. Rat hippocampal neurons, cultured at low density in serum-free medium, were applied to the growth matrix of PA22-2-coated substrates and, within 1-3 h of culture, formed a network-like pattern that more or less matched the printed grid. Reliability and reproducibility of neuronal network formation depended on the geometry, line width and node diameter of the grid pattern. The immobilised neurons showed resting membrane potentials comparable with controls and, already after 1 day of culture, were capable of eliciting action potentials. The suitability of the immobilised neurons for the study of man-made neural networks and for multi-site recordings from a functional neuronal network is discussed.

Animals↗
PubMed2000

Novel histamine H(3)-receptor antagonists with carbonyl-substituted 4-(3-(phenoxy)propyl)-1H-imidazole structures like ciproxifan and related compounds.

Novel histamine H(3)-receptor antagonists possessing a 4-(3-(phenoxy)propyl)-1H-imidazole structure generally substituted in the para-position of the phenyl ring have been synthesized according to Mitsunobu or S(N)Ar reactions. With in vitro and in vivo screening for H(3)-receptor antagonist potency, the carbonyl-substituted derivatives proved to be highly active compounds. A number of compounds showed in vitro affinities in the subnanomolar concentration range, and the 4-hexanoyl (10) and 4-acetyl-3-methyl (29) substituted derivatives showed in vivo antagonist potencies of about 0.1 mg/kg after po administration. Many proxifans were also tested for their affinities at other histamine receptor subtypes thereby demonstrating their pronounced H(3)-receptor subtype selectivity. Since the cyclopropyl ketone derivative 14 (ciproxifan) had high affinity in vitro as well as high potency in vivo, it was selected for further studies in monkeys. It showed good oral absorption and long-lasting, dose-dependent plasma levels making it a promising compound for drug development.

Animals↗
PubMed2000

[Tick-borne meningoencephalitis in Thurgau Canton: a clinical and epidiomological analysis].

BACKGROUND: Tick-borne meningo-encephalitis (TBE) is caused by a flavivirus species that is transmitted from rodents to humans by Ixodes ticks. The clinical picture of central nervous system involvement varies from febrile headache to lethal encephalitis. To date no specific treatment exists, although protective active immunisation is available. METHODS: We present the clinical and epidemiological data from 73 patients with TBE who acquired the infection in Canton Thurgau in the years 1996-1999. RESULTS: Canton Thurgau is a state in eastern Switzerland with a population of 230,000. Within the last five years the reported cases of TBE have increased more than threefold. The area where infectious tick bites were registered has expanded from the western to the eastern part and now encompasses the entire state. The risk of infection is clearly related to frequent activities in wooded areas, though outdoor activities not in forests also carry a considerable risk. In > 80% of the cases a postviral neurasthenic syndrome develops involving absence from work for two months on average. In the elderly and patients who present with encephalitic symptoms, a worse outcome with persistent neurological symptoms or even death has been observed. CONCLUSION: The increasing incidence of TBE, the expansion of infectious ticks to the east and high morbidity justify active immunisation against TBE on a broad scale in Canton Thurgau.

Adolescent↗
PubMed2000

Barrier-to-autointegration factor (BAF) bridges DNA in a discrete, higher-order nucleoprotein complex.

Barrier-to-autointegration factor (BAF) is a highly conserved cellular protein that was identified by its activity in protecting retroviral DNA against autointegration. We show that BAF has the property of bridging double-stranded DNA in a highly ordered nucleoprotein complex. Whereas BAF protein alone is a dimer in solution, upon binding DNA, BAF forms a dodecamer with DNA bound at multiple discrete sites in the complex. The interactions between BAF and DNA are entirely nonspecific with respect to DNA sequence. The dual interaction of BAF with DNA and LAP2, a protein associated with the nuclear lamina, suggests a role for LAP2 in chromosome organization. Consistent with this idea, RNA interference experiments with Caenorhabditis elegans reveal a defect in mitosis.

Animals↗
PubMed2000

The MADS-Box factor CeMEF2 is not essential for Caenorhabditis elegans myogenesis and development.

MEF2 is an evolutionarily conserved MADS (MCM1, Agamous, Deficiens, and serum response factor) box-type transcription factor that plays a critical role in vertebrate and Drosophila melanogaster myogenesis. We have addressed the developmental role of the single MEF2-like factor, CeMEF2, in Caenorhabditis elegans. Using expression assays and two mef-2 deletion alleles, we show that CeMEF2 is not required for proper myogenesis or development. Moreover, a putative null mef-2 allele fails to enhance or suppress the phenotypes of mutants in CeMyoD or CeTwist. Our results suggest that despite its evolutionary conservation of sequence and DNA binding properties, CeMEF2 has adopted a divergent role in development in the nematode compared with Drosophila and vertebrates.

Amino Acid Sequence↗
PubMed2000

Biosynthesis of PF1022A and related cyclooctadepsipeptides.

PF1022A belongs to a recently identified class of N-methylated cyclooctadepsipeptides (CODPs) with strong anthelmintic properties. Described here is the cell-free synthesis of this CODP and related structures, as well as the purification and enzymatic characterization of the responsible synthetase. For PF1022A synthesis extracts of Mycelia sterilia were incubated with the precursors L-leucine, D-lactate, D-phenyllactate, and S-adenosyl-L-methionine in the presence of ATP and MgCl(2). A 350-kDa depsipeptide synthetase, PFSYN, responsible for PF1022A synthesis was purified to electrophoretic homogeneity. Like other peptide synthetases, PFSYN follows a thiotemplate mechanism in which the substrates are activated as thioesters via adenylation. N-Methylation of the substrate L-leucine takes place after covalent binding prior to peptide bond formation. The enzyme is capable of synthesizing all known natural cyclooctadepsipeptides of the PF1022 type (A, B, C, and D) differing in the content of D-lactate and D-phenyllactate. In addition to PF1022 types A, B, C, and D, the in vitro incubations produced PF1022F (a CODP consisting of D-lactate and N-methyl-L-leucine), as well as di-, tetra-, and hexa-PF1022 homologs. PFSYN strongly resembles the well documented enniatin synthetase in size and mechanism. Our results suggest that PFSYN, like enniatin synthetase, is an enzyme with two peptide synthetase domains and forms CODP by repeated condensation of dipeptidol building blocks. Due to the low specificity of the d-hydroxy acid binding site, D-lactate or D-phenyllactate can be incorporated into the dipeptidols depending on the concentration of these substrates in the reaction mixture.

Adenosine Triphosphate↗
PubMed2000

A protein phosphatase is involved in the cholinergic suppression of the Ca(2+)-activated K(+) current sI(AHP) in hippocampal pyramidal neurons.

The slow calcium-activated potassium current sI(AHP) underlies spike-frequency adaptation and has a substantial impact on the excitability of hippocampal CA1 pyramidal neurons. Among other neuromodulatory substances, sI(AHP) is modulated by acetylcholine acting via muscarinic receptors. The second-messenger systems mediating the suppression of sI(AHP) by muscarinic agonists are largely unknown. Both protein kinase C and A do not seem to be involved, whereas calcium calmodulin kinase II has been shown to take part in the muscarinic action on sI(AHP). We re-examined the mechanism of action of muscarinic agonists on sI(AHP) combining whole-cell recordings with the use of specific inhibitors or activators of putative constituents of the muscarinic pathway. Our results suggest that activation of muscarinic receptors reduces sI(AHP) in a G-protein-mediated and phospholipase C-independent manner. Furthermore, we obtained evidence for the involvement of the cGMP-cGK pathway and of a protein phosphatase in the cholinergic suppression of sI(AHP), whereas release of Ca(2+) from IP(3)-sensitive stores seems to be relevant neither for maintenance nor for modulation of sI(AHP).

Animals↗
PubMed2000

Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton.

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76-associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3-coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

Actin-Related Protein 2↗
PubMed2000

A novel H(+)-coupled oligopeptide transporter (OPT3) from Caenorhabditis elegans with a predominant function as a H(+) channel and an exclusive expression in neurons.

We have cloned and functionally characterized a novel, neuron-specific, H(+)-coupled oligopeptide transporter (OPT3) from Caenorhabditis elegans that functions predominantly as a H(+) channel. The opt3 gene is approximately 4.4 kilobases long and consists of 13 exons. The cDNA codes for a protein of 701 amino acids with 11 putative transmembrane domains. When expressed in mammalian cells and in Xenopus laevis oocytes, OPT3 cDNA induces H(+)-coupled transport of the dipeptide glycylsarcosine. Electrophysiological studies of the transport function of OPT3 in Xenopus oocytes show that this transporter, although capable of mediating H(+)-coupled peptide transport, functions predominantly as a H(+) channel. The H(+) channel activity of OPT3 is approximately 3-4-fold greater than the H(+)/peptide cotransport activity as determined by measurements of H(+) gradient-induced inward currents in the absence and presence of the dipeptide using the two-microelectrode voltage clamp technique. A downhill influx of H(+) was accompanied by a large intracellular acidification as evidenced from the changes in intracellular pH using an ion-selective microelectrode. The H(+) channel activity exhibits a K(0.5)(H) of 1.0 microM at a membrane potential of -50 mV. At the level of primary structure, OPT3 has moderate homology with OPT1 and OPT2, two other H(+)-coupled oligopeptide transporters previously cloned from C. elegans. Expression studies using the opt3::gfp fusion constructs in transgenic C. elegans demonstrate that opt3 gene is exclusively expressed in neurons. OPT3 may play an important physiological role as a pH balancer in the maintenance of H(+) homeostasis in C. elegans.

Acids↗