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Biomedical subjects

K Müller

Publications and source records attributed to K Müller.

At least 145 records · Page 8Linked to original sources
PubMed1998

Improved identification of mycobacteria by using the microbial identification system in combination with additional trimethylsulfonium hydroxide pyrolysis.

The MIDI automated Microbial Identification System (MIS) uses gas chromatography (GC) analysis of whole-cell fatty acid methyl esters (FAMEs) between 9 and 20 carbons in length to characterize a wide range of bacterial genera and species, including mycobacteria. Mycolic acid cleavage products (MACPs) with chain lengths of C22 to C26 are not released by MIDI sample preparation of mycobacteria. Therefore, the MIS library search report often matches several mycobacterial species without any significant difference in the similarity indices. The problem is solved by adding trimethylsulfonium hydroxide (TMSH) instead of sodium sulfate in the last step of sample preparation, thus allowing the identification of MACPs in addition to FAMEs. Only one GC run parameter has to be changed: the temperature program must be extended from 260 to 310 degrees C. The MIS library search report for the identification of bacteria is not disturbed by TMSH. The combination of conventional library search report with the information of typical MACP patterns yields significantly better discrimination of mycobacterial species than the MIDI method allows.

Chromatography, Gas↗
PubMed1998

Glucose-modified low density lipoprotein enhances human monocyte chemotaxis.

In diabetes mellitus the progression of atherosclerosis is accelerated. The interaction of glucose with atherogenic lipoproteins may be relevant to the mechanisms responsible for this vascular damage. The aim of this study was to examine the effect of glucose-modified low density lipoprotein (LDL) on human monocyte chemotaxis and to investigate the roles of oxidation and glycation in the generation of chemotactic LDL. Cu(II)-mediated LDL oxidation was potentiated by glucose in a dose-dependent manner and increased its chemotactic activity. Incubation with glucose alone, under conditions where very little oxidation was observed, also increased the chemotactic property of LDL. Neither diethylenetriamine pentaacetic acid (DETAPAC) nor aminoguanidine, which both inhibited LDL oxidation, completely inhibited the chemotactic activity of glycated oxidised LDL. The results suggest that both oxidation and glycation contribute to increased chemotactic activity.

Chelating Agents↗
PubMed1998

Effects of the bisphosphonate zoledronate on bone loss in the ovariectomized and in the adjuvant arthritic rat.

The effect of the bisphosphonate zoledronate (CAS 118072-93-8, CGP 42446) on trabecular bone in two rat models of osteopenia, i.e. the ovariectomized rat and the adjuvant arthritic rat, was tested and compared to the activity of alendronate and pamidronate. All three bisphosphonates prevented bone loss in the distal femur and in the lumbar vertebrae in both animal models, as measured by chemical analysis and/or bone densitometry. Zoledronate was the most potent bisphosphonate, 10-30 times more potent than alendronate and 120 times more potent than pamidronate.

Absorptiometry, Photon↗
PubMed1998

Anthranoid free radicals found in pseudomelanosis coli.

Pseudomelanosis coli occurs after prolonged intake a anthranoids. After discontinuation of intake the pigmentation disappears apparently without noxious effects, including carcinogenicity and genotoxicity. We are presenting ESR spectra of pseudomelanosis coli specimen, compared to ESR spectra of pigmented skin scales taken from psoriatic patients treated topically with anthralin, and with ESR spectra of anthralin brown material formed in vitro. The ESR spectra show comparable g values within the accuracy of measurements. The examined specimens reveal remarkable stability: the intensity of the ESR signal remained practically constant over the period of four years. The chemical and physicochemical properties of the brown pigments formed from anthranoids explain the observed bio-inertness of these materials including that of melanosis coli pigment derived from anthranoids.

Administration, Topical↗
PubMed1997

Simple analogues of anthralin: unusual specificity of structure and antiproliferative activity.

Fifty-nine simple analogues of the antipsoriatic agent, anthralin, have been prepared by modifying the positions of the 1,8-hydroxyl groups, replacement of the hydroxyl groups, substitution at the oxygen functions, introduction of additional functional groups into various positions of the anthracenone nucleus, or removal of particular structural elements. The compounds were evaluated for their antiproliferative action against human keratinocytes and inhibition of the generation of leukotriene B4 in polymorphonuclear leukocytes, which may be useful to resolve the proliferative and inflammatory aspects of psoriasis, respectively. Even though many anthracenones were more potent inhibitors of leukotriene biosynthesis than anthralin, none of the compounds was substantially more effective as this drug in suppressing keratinocyte cell growth. There is an absolute requirement for two hydroxyl groups peri to a hydrogen bond acceptor such as a keto or an imino group for high potency. In addition to further delineating the nature of the pharmacophore for this class of compounds, also naphthalenedione with a peri hydroxyl group was identified as a pharmacophore with antiproliferative activity against keratinocyte growth.

Administration, Topical↗
PubMed1997

Antipsoriatic anthrones with modulated redox properties. 4. Synthesis and biological activity of novel 9,10-dihydro-1,8-dihydroxy-9-oxo-2-anthracenecarboxylic and -hydroxamic acids.

A novel series of carboxylic and hydroxamic acids based on 1,8-dihydroxy-9(10H)-anthracenone were synthesized from 8-hydroxy-1-methoxy-9,10-anthracenedione as the key intermediate and evaluated both in the bovine polymorphonuclear leukocyte 5-lipoxygenase (5-LO) assay and in the HaCaT keratinocyte proliferation assay for their enzyme inhibitory and antiproliferative activity, respectively. The most potent inhibitors in both assays were the N-methylated hydroxamic acids 5d-8d with straight chain alkyl spacers. Incorporation of these structural features on the anthracenone pharmacophore resulted in increased inhibitory activity against 5-LO while the antiproliferative activity was retained. In addition, prooxidant properties as measured by deoxyribose degradation and cytotoxicity as assessed by LDH release were largely reduced as compared with the antipsoriatic anthralin. Contrary to anthralin, antioxidant properties were observed as documented by the reactivity of the novel compounds against free radicals and inhibition of lipid peroxidation in model membranes.

Animals↗
PubMed1997

Antipsoriatic and proinflammatory action of anthralin. Implications for the role of oxygen radicals.

Anthralin is among the most effective agents for the topical treatment of psoriasis. However, this drug causes unpleasant side-effects such as inflammation and staining of the nonaffected skin surrounding a psoriatic lesion. The biochemical basis for the induction of an inflammatory response in the skin and the antipsoriatic effectiveness are uncertain, although several cellular targets of anthralin action have been identified. Because no single mechanism is operative, the view was taken that all the effects exerted by anthralin are caused by its redox activity leading to the generation of anthralin free radicals and oxygen radicals. Clear relationships between oxygen-radical production by anthralin and biological response are evident with respect to chemical lesions in cellular macromolecules such as DNA, lipid membranes, and enzymes, indicating that these species account for the antipsoriatic and proinflammatory effects elicited by anthralin. This poses new challenges for the medicinal chemist and provides impetus for identifying novel compounds having potential for an improved therapeutic index.

Anthralin↗
PubMed1997

Aspartate, glutamate, glutamine, glycine and gamma-aminobutyric acid in human bioptic neocortical areas: comparison to autoptic tissue.

Amino acid concentrations were determined by high performance liquid chromatography in distinct areas of human neocortex of autoptic and bioptic origin. The concentrations in autoptic tissue were similar in all cortical areas which may be explained by postmortem proteolysis, abolishing regional differences seen in bioptic tissue. Aspartate, glutamate, glycine and gamma-aminobutyric acid concentrations were lower, but glutamine levels were higher, in biopsied than in autopsied tissue. Glycine and gamma-aminobutyric acid concentrations increased with the age of biopsied patients. The differences seen suggest that only amino acid concentrations determined in bioptic tissue may yield a reliable data base for the interpretation of pathological alterations in neocortical biopsies of patients with brain diseases.

Adult↗
PubMed1997

Evaluation of purine nucleotide loss, lipid peroxidation and ultrastructural alterations in post-hypoxic hepatocytes.

1. Hypoxic alterations in isolated rat hepatocytes were demonstrated by a 90% ATP loss during 60 min of ischaemia and temporary increases of nucleotide degradation products. 2. The oxidative stress during reoxygenation was demonstrated in these cells by a decrease in reduced glutathione (GSH) concentration (30%) and a threefold increase in lipid peroxidation products such as 4-hydroxynonenal and thiobarbituric acid-reactive substances (TBA-RSs). The tremendous GSH loss could not be balanced by the slight oxidized glutathione (GSSG) increase during reoxygenation. 3. For the first time the involvement of free radicals was directly demonstrated using electron spin resonance (ESR) spectroscopy in reoxygenated liver cells. Using the spin trap 5,5-dimethylpyrroline-1-oxide (DMPO), a carbon-centred radical and the adduct of the hydroxyl radical could be detected during early reoxygenation. 4. Morphological alteration of cells was observed, beginning during hypoxia and increasing during post-hypoxic reoxygenation. Electron microscopic findings of hypoxic and post-hypoxic cell damage included pyknosis of nuclei, spherical transformation of mitochondria and increased number of vesicles.

Aldehydes↗
PubMed1997

Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment.

To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 microg/kg) or pamidronate (3.7-370 microg/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure.

Animals↗
PubMed1997

Ontogeny of ipsilateral corticospinal projections: a developmental study with transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) has been used to describe the maturation of the corticospinal tract in children. Ipsilateral corticospinal connections have been demonstrated with TMS in patients with congenital mirror movements, in patients after hemispherectomy, and in children with hemiplegic cerebral palsy. The goal of the study was to find out whether corticospinal ipsilateral projections in children can be demonstrated during the first decade of life as part of normal ontogeny. For this purpose, we examined 50 normal children (age range, 3-11 years) with focal TMS over the left and right hemispheres to target muscles in proximal and distal parts of the upper extremity (first dorsal interosseus, biceps brachii, and brachioradialis). To lower the stimulation threshold, we stimulated under voluntary preinnervation. In two-thirds of the children we elicited ipsilateral motor evoked potentials (MEPs). This occurred more often in proximal than in distal muscles. The latency of the ipsilateral MEPs was about 12 to 14 msec longer than the usual contralateral response. From the age of 10, and in adults, ipsilateral MEPs could not be detected. Also considering lesion data from adult patients, the most likely explanation for the disappearance of ipsilateral corticospinal connections after the age of 10 years is an increasing transcallosal inhibitory influence during development. The presence of ipsilateral corticospinal connections appears to be a normal state in ontogeny.

Adult↗
PubMed1997

Specific properties of the extracellular chondroitin sulphate proteoglycans in the mandibular condylar growth centre in pigs.

The developing condylar cartilage of the temporomandibular joint responds to changes in load by adaptive growth. Because local regulatory events taking place during growth processes are not well understood, investigation of extracellular matrix composition could provide new information about which matrix molecules are involved in the regulation of growth processes in this avascular tissue. The large chondroitin sulphate-rich proteoglycans in the mandibular condyle were compared to the proteoglycans in the weight-bearing femoral condyle of juvenile domestic pigs with respect to their buoyant density, chemical composition and immunological identity after isolation by dissociative extraction and CsCl density-gradient centrifugation. The distribution of these proteoglycans was studied in cryosections of mandibular condyle by immunohistochemistry using polyclonal antibodies produced against pig large proteoglycans. In the mandibular condyle, predominantly in the articular zone, the relative amount of proteoglycans with a low glycosaminoglycan content was greater than in femoral cartilage. The large proteoglycan immunologically related to aggrecan gave a protein core of 450 kDa after enzymatic deglycosylation and clearly possessed less keratan sulphate than in femoral aggrecan. Furthermore, the mandibular tissue contained another large proteoglycan with a protein core of 550 kDa after enzymatic deglycosylation, which was immunologically related to the fibroblast-like versican. Immunohistochemistry showed aggrecan increasing in amount inferiorly. In contrast, "versican' was exclusively found in the fibrous and differentiation layers. Aggrecan is mainly responsible for shock absorption and versican and its homologues may be involved in the control of cell proliferation and differentiation. Thus the matrix components of the mandibular condyle seem to be adapted to its special functional needs including parallel articulation and growth.

Aggrecans↗
PubMed1997

Effects of reactive oxygen species on the biosynthesis of 12 (S)-hydroxyeicosatetraenoic acid in mouse epidermal homogenate.

Arachidonic acid is converted to 12-hydroxyeicosatetraenoic acid (12-HETE) in a homogenate of mouse epidermal cells. When the epidermal homogenate was preincubated with scavengers of reactive oxygen species (ROS), catalase or superoxide dismutase, significantly larger amounts of 12-HETE were produced as compared to untreated controls, suggesting that 12-lipoxygenase is quite prone to inactivation by ROS and peroxides. Mouse epidermal homogenate was then exposed to nine different ROS-generating systems to study the effects of superoxide, hydrogen peroxide, singlet oxygen, hypochlorite, peroxyl radicals, and alkyl hydroperoxides on the enzyme activity. Analysis by chiral phase high performance liquid chromatography demonstrated that the 12-HETE biosynthesized from arachidonic acid by mouse epidermal homogenate was the 12 (S)-enantiomer and excludes oxidation of arachidonic acid by ROS in a nonspecific free radical mechanism which leads to racemic 12-HETE. ROS generated by the interaction of xanthine with xanthine oxidase strongly inhibited epidermal 12 (S)-HETE biosynthesis. A flux of 0.7 nmol of superoxide/min/ml of reaction medium resulted in more than 50% inhibition of epidermal 12-lipoxygenase activity. The decrease in 12 (S)-HETE biosynthesis appeared to involve both superoxide and hydrogen peroxide. The efficacy of the latter species was also documented by exposure of mouse epidermal 12-lipoxygenase to glucose and glucose oxidase, which resulted in similar inhibitory effects on 12 (S)-HETE biosynthesis. The presence of the iron chelator diethylenetriaminepentaacetic acid during incubation of epidermal 12-lipoxygenase with both the xanthine/xanthine oxidase or the glucose/glucose oxidase systems partially protected the enzyme against inhibition, indicating that hydroxyl radical contributes to the overall inhibitory effect. Also, organic hydroperoxides inhibited epidermal 12-lipoxygenase, whereas singlet oxygen, hypochlorite, and peroxyl radicals were not effective. The results of this study lead to the proposal that 12-lipoxygenase activity may be regulated by ROS such as hydrogen peroxides, superoxide, and hydroxyl radicals.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1997

Clonal descent and microevolution of Neisseria meningitidis during 30 years of epidemic spread.

Serogroup A meningococci of subgroups III, IV-1 and IV-2 are probably descended from a common ancestor that existed in the nineteenth century. The 10.5kb sequences spanning five distinct chromosomal loci, encoding cell-surface antigens, a secreted protease or housekeeping genes and intergenic regions, were almost identical in strains of those subgroups isolated in 1966, 1966 and 1917 respectively. During the subsequent two to three decades, all of these loci varied as a result of mutation, translocation or import of DNA from unrelated neisseriae. Thus, microevolution occurs frequently in naturally transformable bacteria. Many variants were isolated only once or within a single geographical location and disappeared thereafter. Other variants achieved genetic fixation within months or a few years. The speed with which sequence variation is either eliminated or fixed may reflect sequential bottlenecks associated with epidemic spread and contrasts with the results of phylogenetic analyses from bacteria that do not cause epidemics.

Alleles↗