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Biomedical subjects

J Nickel

Publications and source records attributed to J Nickel.

At least 19 recordsLinked to original sources
PubMed2002

[Well-informed on health matters--how well? The German 'Clearinghouse for Patient Information'--objective, background and methods].

OBJECTIVE: Health information for lay people in print or electronic form are internationally recognised as useful tools and as necessary in the decision-making process of individuals. The effectiveness of offered patient information depends on quality and accessibility. Because much of the available health information is significantly deficient, the Agency for Quality in Medicine developed a programme for assessing the quality of specialised health and medical information for all non-medically trained persons. The German 'Clearinghouse for Patient Information' project is an adjunct to the already established German 'Clearinghouse for Clinical Guidelines'. METHOD: The basis for quality improvement for specialised medical information consists 1. in the determination of demands on quality for patient information published in the German language, 2. development of a standardised instrument for assessing the quality of specialised medical information by non-medically trained persons, 3. establishment of an Internet portal for evaluated and rated material, and 4. the establishment and organisation of relevant partnerships with information providers and users of health and medical information. The principle building block to rate medical information for lay people are the DISCERN criteria for good patient information. The results of the quality rating of specialised medical information are made available to the public with emphasis on promoting transparency of the assessment and rating processes used. RESULTS: The Internet-based patient information service of the Agency for Quality in Medicine (www.patienten-information.de 19.06.02) has currently a selection of approximately 800 information items covering fifty disease topics with fully or partially evaluated and rated information. Partnerships to appropriate information providers and users are already established and have been tested in special single projects. CONCLUSION: To advance the process of quality improvement for medical information for non-medical and lay persons, it is essential to develop and to intensify the cooperation with stake holders and partners at different levels. Only through close cooperation with others it is possible to create a basis to continuously develop and improve the information quality assessment instrument further. In addition, effective strategies need to be developed to disseminate these endeavours to patients and consumers of health information in a user-friendly and transparent way.

Evidence-Based Medicine↗
PubMed2001

Neural correlates of religious experience.

The commonsense view of religious experience is that it is a preconceptual, immediate affective event. Work in philosophy and psychology, however, suggest that religious experience is an attributional cognitive phenomenon. Here the neural correlates of a religious experience are investigated using functional neuroimaging. During religious recitation, self-identified religious subjects activated a frontal-parietal circuit, composed of the dorsolateral prefrontal, dorsomedial frontal and medial parietal cortex. Prior studies indicate that these areas play a profound role in sustaining reflexive evaluation of thought. Thus, religious experience may be a cognitive process which, nonetheless, feels immediate.

Adult↗
PubMed2001

The crystal structure of the BMP-2:BMPR-IA complex and the generation of BMP-2 antagonists.

BACKGROUND: Bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs) belong to the large transforming growth factor-beta (TGF-beta) superfamily of multifunctional cytokines. Signaling of the BMPs requires the binding of the BMP to the BMP cell surface receptors BMPR-IA, BMPR-IB, and BMPR-II. Similar to other cytokines, members of the TGF-beta superfamily exhibit stringent specificity in their ligand-receptor interactions, which may be a reason for the qualitative and quantitative differences in cellular responses. To understand how BMPs and GDFs activate their receptors, it is important to determine structure and binding mechanisms of ligand-receptor complexes. We have used BMP-2 as a key representative of the BMPs to identify the epitopes for type I and type II receptor binding by mutational interaction analyses and have solved the crystal structure of a BMP2:BMPR-IA receptor ectodomain complex. METHODS: To identify amino acid side chains involved in receptor binding, a collection of in vitro mutagenized human BMP-2 variants was prepared and subjected to interaction analyses with use of the receptor ectodomains of BMPR-IA, BMPR-II, and ActR-II immobilized on a biosensor system. The biological activity of the BMP-2 variants was measured by BMP-2 dependent expression of alkaline phosphatase (ALP) in C2C12 cells. For crystallization, a complex of BMP-2 and the ectodomain of BMPR-IA was formed in solution, purified, and crystallized as described(12). RESULTS: The ligand-receptor interaction analysis of the BMP-2 variants identified distinct epitopes for type I and type II receptor binding. Because the structure of TGF-beta-like proteins has been compared with that of an open hand, the binding epitope for the type I receptor was-on the basis of its location-termed "wrist" epitope. The crystal structure of the BMP-2:BMPR-IA ectodomain complex revealed a key feature of the ligand-receptor interaction: a large hydrophobic residue (Phe85) within a hydrophobic patch of BMPR-IA fit into a hydrophobic pocket composed of residues of both BMP-2 monomers. A second epitope identified by alanine mutagenesis scanning was termed the "knuckle" epitope on the basis of its location on the outer side of the "finger" segments of BMP-2. Mutations in either the wrist epitope or the knuckle epitope produced variants with altered biological activities. Variants with antagonistic properties were exclusively generated by mutations in the knuckle epitope of BMP-2. CONCLUSIONS AND CLINICAL RELEVANCE: The identification and characterization of the two receptor binding epitopes in BMP-2 provide new insight into the primary steps of BMP-receptor activation. Because of the structural similarities between members of the TGF-beta superfamily, it can be assumed that the data presented in this work are transferable to other TGF-beta receptor systems. Because of the association with various diseases, the generation of antagonists of other TGF-beta superfamily members might generate potent tools for basic research and therapeutic approaches.

Amino Acid Sequence↗
PubMed2000

Similar effects of electroporational stress and treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate on vimentin expression in mouse plasmacytoma cells.

In mouse plasmacytoma cells (MPC-11), an activation of the normally repressed vimentin gene was observed as a response to transfectional stress. Effects of electroporation on vimentin gene expression were compared at the cellular and chromatin level to those caused by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). At the cellular level, similar changes in vimentin gene activity and cell-cycle distribution were observed by flow cytometry, whereas at the chromatin level similar changes in patterns of hypersensitive regions were detected by DNase I mapping. Additionally, a region located 700 bp upstream of the transcriptional start became hypersensitive to DNase I digestion upon electroporation and TPA treatment. This region overlaps two adjacent AP-1-like binding elements and generates specific DNA/AP-1 complexes in bandshift experiments. Therefore, the transcription factor AP-1 seems to play a central role in the activation of vimentin gene expression induced by these 2 different forms of stress.

Animals↗
PubMed2000

BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II.

Bone morphogenetic protein-2 (BMP-2) induces bone formation and regeneration in adult vertebrates and regulates important developmental processes in all animals. BMP-2 is a homodimeric cysteine knot protein that, as a member of the transforming growth factor-beta (TGF-beta) superfamily, signals by oligomerizing type I and type II receptor serine-kinases in the cell membrane. The binding epitopes of BMP-2 for BMPR-IA (type I) and BMPR-II or ActR-II (type II) were characterized using BMP-2 mutant proteins for analysis of interactions with receptor ectodomains. A large epitope 1 for high-affinity BMPR-IA binding was detected spanning the interface of the BMP-2 dimer. A smaller epitope 2 for the low-affinity binding of BMPR-II was found to be assembled by determinants of a single monomer. Symmetry-related pairs of the two juxtaposed epitopes occur near the BMP-2 poles. Mutations in both epitopes yielded variants with reduced biological activity in C2C12 cells; however, only epitope 2 variants behaved as antagonists partially or completely inhibiting BMP-2 activity. These findings provide a framework for the molecular description of receptor recognition and activation in the BMP/TGF-beta superfamily.

Amino Acid Sequence↗
PubMed2000

Isolation of recombinant BMP receptor IA ectodomain and its 2:1 complex with BMP-2.

Bone morphogenetic protein-2 (BMP-2) is a member of the transforming growth factor beta superfamily which induces bone formation and regeneration, and important steps during early embryonic development. BMP-2 signals via oligomerization of type I and type II serine/threonine kinase receptors. We report here expression of the extracellular domain of the human type IA receptor for BMP-2 (BMPR-IA) in Escherichia coli. This soluble form of BMPR-IA (sBMPR-IA) was purified employing a BMP-2 affinity column. Gel filtration experiments and analysis of gel filtration fractions by polyacrylamide electrophoresis and densitometry reveal that BMP-2 forms a defined 1:2 complex with sBMPR-IA that can be purified and hopefully used for crystallization studies.

Binding Sites↗
PubMed2000

Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis.

Aberrant apoptosis-mediated cell death is believed to result in a number of different human diseases. For example, excessive apoptosis in the liver can result in fulminant and autoimmune forms of hepatitis. We have explored the possibility that inhibition of Fas expression in mice would reduce the severity of fulminant hepatitis. To do this, we have developed a chemically modified 2'-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 22023) inhibitor of mouse Fas expression. In tissue culture, this oligonucleotide induced a reduction in Fas mRNA expression that was both concentration- and sequence-specific. In Balb/c mice, dosing with ISIS 22023 reduced Fas mRNA and protein expressions in liver by 90%. The ID50 for this response was 8-10 mg kg-1 daily dosing, and the reduction was highly dependent on oligonucleotide sequence, oligonucleotide concentration in liver, and treatment time. Pretreatment with ISIS 22023 completely protected mice from fulminant hepatitis induced by agonistic Fas antibody, by a mechanism entirely consistent with an oligonucleotide antisense mechanism of action. In addition, oligonucleotide-mediated suppression of Fas expression reduced the severity of acetaminophen-mediated fulminant hepatitis, but was without effect on concanavalin A-mediated hepatitis. Our results demonstrate that 2'-O-(2-methoxy)ethyl containing antisense oligonucleotides targeting Fas can exert in vivo pharmacological activity in liver, and suggest that oligonucleotide inhibitors of Fas may be useful in the treatment of human liver disease.

Animals↗
PubMed2000

A comparison of bolus versus continuous cardiac output in an experimental model of heart failure.

OBJECTIVE: The majority of studies examining cardiac output measurement have been done in physiologically stable models with low thermal background noise. Research comparing continuous cardiac output (CCO) with bolus thermodilution cardiac output (COTD) measures in human and animal models have reported high correlations, negligible bias, but large limits of agreement. The purpose of this project was to compare CCO with COTD measures in an experimental model of heart failure where the cardiac output values were low and the range was narrow. DESIGN: A one-group experimental design with preintervention control measures and repeated CCO and COTD measures across nine time points. SETTING: Cardiovascular research laboratory. SUBJECTS: Thirty dogs. MEASURES AND MAIN RESULTS: Univariate and multivariate versions of repeated-measures analysis were used to assess the influences of temperature, weight, and stage of the experimental protocol on CCO, COTD, and the differences between them. The two measures CCO and COTD were assessed for agreement by using methods proposed by Bland and Altman. Two hundred and fifty pairs of measurements were obtained during sinus rhythm. The range for COTD measures was 0.5-4.67 L/min and for CCO measures 1.0-5.40 L/min. Of the 250 cardiac outputs estimated by the continuous method, 73.4% of the values were within +/-15% of that estimated by the repetitive, single thermodilution method. The mean bias for the entire protocol was 0.01 (SD = 0.51) with a range of 4.33 L/min. CONCLUSION: Agreement between the two measures may be the function of biological variability, responses to anesthesia, and technique. Bland and Altman evaluation demonstrated low bias and precision and similar levels of agreement when compared with previous studies in an experimental model where the cardiac output was low and the range was narrow.

Animals↗
PubMed1998

Monoclonal antibodies SMI 311 and SMI 312 as tools to investigate the maturation of nerve cells and axonal patterns in human fetal brain.

Neurofilaments, which are exclusively found in nerve cells, are one of the earliest recognizable features of the maturing nervous system. The differential distribution of neurofilament proteins in varying degrees of phosphorylation within a neuron provides the possibility of selectively demonstrating either somata and dendrites or axons. Non-phosphorylated neurofilaments typical of somata and dendrites can be visualized with the aid of monoclonal antibody SMI 311, whereas antibody SMI 312 is directed against highly phosphorylated axonal epitopes of neurofilaments. The maturation of neuronal types, the development of area-specific axonal networks, and the gradients of maturation can thus be demonstrated. Optimal immunostaining with SMI 311 and SMI 312 is achieved when specimens are fixed in a mixture of paraformaldehyde and picric acid for up to 3 days and sections are incubated free-floating. Neurons, with their dendritic domains immunostained by SMI 311 in a Golgi-like manner, can be completely visualized in relatively thick sections. The limitations of Golgi-preparations, such as glia-labeling, artifacts, and the staining of only a small non-representative percentage of existing neurons, are not apparent in SMI preparations, which additionally provide the possibility of selectively staining axonal networks. The results achieved in normal fetal brain provide the basis for studies of developmental disturbances.

Abortion, Induced↗
PubMed1998

Alterations in myelin formation in fetal brains of twins.

Insufficient nutrition is known to lead to disturbances in postnatal myelin formation. This study aims to demonstrate that early myelination is altered in human twin pregnancies. Five brains of twins with a symmetric blood supply and three brains of twins with chronic fetal-fetal transfusion syndrome (one hypervolemic acceptor and two hypoxemic donors) were investigated and compared with six brains of singletons. The globus pallidus, where myelination normally starts within the prosencephalon, was studied immunohistochemically using antibodies against myelin basic protein (MBP) and with the aid of electron microscopy. In twins and donors, MBP-immunostained somata of myelin-forming oligodendrocytes were packed densely within the globus pallidus, whereas in singletons and acceptors an intense fibrous immunoreactivity was observed. Electron micrographs revealed noncompacted myelin in twins, whereas in singletons the multilaminar structure of compact myelin was observed. The results demonstrate a distinct qualitative alteration in myelination because of nutritional insufficiency during pregnancy. The lack of MBP-positive fibers (i.e., compact myelin sheaths) may be correlated to impaired maturation of oligodendroglia. The alterations described here may reflect a delayed incorporation of MBP into the processes so that the formation of compact myelin is retarded.

Brain↗
PubMed1998

Transient features of the thalamic reticular nucleus in the human foetal brain.

The architectonic organization and neuronal types of the human foetal reticular nucleus (RN)--with special reference to transient characteristics--have been investigated using antisera against calretinin, parvalbumin and neurofilament epitopes of somata and dendrites (SMI 311). The RN consists of four subdivisions (clearly distinguishable in the 6/7th gestational month): The main portion appears as a prominent structure on account of its extension and high packing density of neurons which coexpress calretinin and parvalbumin. These two calcium-binding proteins are also expressed by the perireticular nucleus forming a conspicuous grey within the internal capsule. Perireticular cells form clusters which are in continuity with the main portion, globus pallidus, ganglionic eminence and pregeniculate nucleus. In double-labellings, a medial subnucleus stands out distinctly as it only expresses calretinin. SMI 311-immunopreparations show neurons revealing a high degree of diversification and elaborated dendritic trees. Several transient characteristics become obvious: the perireticular nucleus, not visible in the adult, represents a distinct entity in the human foetal brain. The main portion and the pregeniculate nucleus appearing as prominent greys are dramatically reduced in size later on. The percentage of RN-neurons expressing calretinin, the diversity of neuronal types and elaborated dendritic trees are reduced. The transient features can be correlated with the RN's putative functional roles in development: early RN-afferents to the dorsal thalamus may represent pioneer fibres providing guiding cues for outgrowing axons from or into the thalamus. Moreover, the RN may serve as an intermediate target for growing axons which are sorted and directed towards different final targets.

Antibodies, Monoclonal↗
PubMed1997

Cis-elements required for the demethylation of the mouse M-lysozyme downstream enhancer.

The mouse lysozyme downstream enhancer was previously colocalized with the DNase I-hypersensitive site in the chromatin of mature macrophages. This hypersensitive site was shown to be macrophage differentiation-dependent. Demethylation of CpG sequences within the enhancer is correlated with lysozyme expression in mature macrophages. Binding of the GABP heterotetrameric transcription factor to the enhancer core element (MLDE), only seen in vivo on the demethylated MLDE element in macrophages, is inhibited by DNA methylation. Here, we analyzed the DNA sequences required for demethylation. In electrophoretic mobility shift experiments we found that in addition to the complete methylated MLDE the hemimethylated form of the lower strand inhibits GABP binding as well. Therefore, GABP is unlikely to be the mediator of demethylation. In addition, we show by stable DNA transfections of methylated mouse lysozyme enhancer sequences that MLDE-flanking sequences are required for demethylation. We narrowed down these DNA elements to two short regions of 163 and 79 base pairs on either side of the MLDE, each of which is sufficient to mediate demethylation of the GABP site.

Animals↗
PubMed1996

Lysozyme gene expression and regulation.

Analysis of lysozyme gene expression in chicken and mouse identified two evolutionarily different mechanisms of lysozyme gene regulation. The lysozyme gene in chicken is expressed in the oviduct and macrophage cells with expression regulated by different, partially overlapping sets of tissue specific cis-acting elements. In contrast to chicken, the mouse genome contains two lysozyme genes generated by a gene duplication event allowing each gene to be regulated by its own regulatory region. One gene is expressed in macrophages, the other in Paneth cells of the small intestine. The macrophage-specific gene contains a single strong enhancer in the 3'-flanking sequences that interacts with ubiquitously factors. Cytosine methylation of the core enhancer sequence has been implicated in the regulation of the enhancer activity. In spite of these evolutionary regulatory differences, the chicken lysozyme transgene retains macrophage-specific expression in mice.

Animals↗
PubMed1996

In vivo protein interaction with the mouse M-lysozyme gene downstream enhancer correlates with demethylation and gene expression.

Differentiation of myeloid precursor cells results in transcriptional activation of the myeloid-specific murine M-lysozyme gene. M-lysozyme gene expression depends on the differentiation state of the myeloid cells and provides a marker for myeloid leukemias. The mouse lysozyme downstream enhancer (MLDE) was colocalized previously with the DNase I hypersensitive site in the chromatin of mature macrophages and shown to be macrophage differentiation-dependent. The correlation of the hypersensitive site appearance with expression of the M-lysozyme gene suggests that the enhancer becomes activated during macrophage differentiation. However, the predominant MLDE-binding protein GABP is ubiquitously expressed, indicating that additional regulatory mechanisms are required for restricting the tissue-specific activity of the enhancer. To demonstrate the specificity of the enhancer in vivo, we examined the in vivo interaction of factors with the MLDE in T cells, immature macrophage cells, and in macrophage cells. Although identical DNase I protection activity is present in extracts from all tested cell lines in vitro, the in vivo interaction of proteins is restricted to mature macrophage cells. The presence of factors capable of interacting with the enhancer is not sufficient for enhancer activity, suggesting that the process of differentiation results in factor accessibility for the MLDE. Analysis of the MLDE methylation state revealed a correlation between demethylation of the single CpG dinucleotide within the MLDE sequence and the in vivo interaction of proteins.

Animals↗
PubMed1995

A fraction enriched in a novel glucocorticoid receptor-interacting protein stimulates receptor-dependent transcription in vitro.

Glucocorticoids influence numerous cell functions by regulating gene activity. The glucocorticoid receptor (GR) is a ligand-activated transcription factor and, like any other transcription factor, does not modulate gene activity just by binding to DNA. Interaction with other proteins is probably required to enhance the establishment of a functional transcription initiation complex. To identify such proteins, we analyzed the in vitro interaction of the glucocorticoid receptor bound to a double glucocorticoid response element with nuclear proteins and describe here three interacting proteins with different molecular weights. One of them, which we named GRIP 170 (GR-interacting protein), was purified and microsequenced, and it turned out to be an unknown protein. When tested in a cell-free transcription assay, the fraction highly enriched for GRIP 170 does not influence basal promoter activity but does enhance GR induction.

Carrier Proteins↗
PubMed1995

Methylation of the mouse M-lysozyme downstream enhancer inhibits heterotetrameric GABP binding.

Expression of the mouse M-lysozyme gene is a specific marker for the differentiation of macrophage/granulocyte cell lineages. Analysis of the mechanisms regulating M-lysozyme gene expression revealed an enhancer element in the 3'-flanking region of the gene, termed the M-lysozyme downstream enhancer (MLDE). Here we demonstrate that the nuclear factors binding to MLDE are present in all tested myeloid and non-myeloid mouse cell lines. Sequence analysis of MLDE identified two different sequences, CAGGAAGT and CCGGAAGT, which match the consensus binding sequences for proteins of the ets gene superfamily. The two sites are oriented palindromicly and separated by 10 bp. DMS/DEPC interference assays revealed different patterns of DNA-protein contacts on the two sites. Mutation of each consensus sequence leads to an individual change in protein binding in vitro. Despite these differences, both sequences are bound by GABP, forming a heterotetrameric complex. Tissue specificity is correlated with demethylation of a single CpG dinucleotide located in one of the two Ets motifs. This site when methylated inhibits GABP binding to both sequences in non-macrophage cell types.

Animals↗
PubMed1991

[Complete airway obstruction by a prosthesis powder. The problem of protecting the airway in emergency service].

An extraordinary occurrence of death is reported due to blocking of the entrance of the larynx by a denture adhesive. The improper usage of this material by a mentally disturbed woman of 66 years of age caused her death by suffocation. In such a case an intubation can involve a transfer of the viscous material to the larynx. Therefore a coniotomy or a tracheotomy should be performed.

Adhesives↗