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Biomedical subjects

U Koch

Publications and source records attributed to U Koch.

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

Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1.

Notch-1 signaling is essential for lymphoid progenitors to undergo T cell commitment, but the mechanism has not been defined. Here we show that thymocytes ectopically expressing Lunatic Fringe, a modifier of Notch-1 signaling, induce lymphoid progenitors to develop into B cells in the thymus. This cell fate switch resulted from Lunatic Fringe-mediated inhibition of Notch-1 function, as revealed by experiments utilizing lymphoid progenitors in which Notch-1 activity was genetically manipulated. These data identify Lunatic Fringe as a potent regulator of Notch-1 during the T/B lineage decision and show that an important function of Notch-1 in T cell commitment is to suppress B cell development in the thymus.

Animals↗
PubMed2001

Measurement of homonuclear three-bond J(H(N)Halpha) coupling constants in unlabeled peptides complexed with labeled proteins: application to a decapeptide inhibitor bound to the proteinase domain of the NS3 protein of hepatitis C virus (HCV).

A new isotope-filtered experiment has been designed to measure homonuclear three-bond J(H(N)Halpha) coupling constants of unlabeled peptides complexed with labeled proteins. The new experiment is based on the 3D HNHA pulse scheme, and belongs to the 'quantitative J-correlation' type. It has been applied to a decapeptide inhibitor bound to the proteinase domain of the NS3 protein of human hepatitis C virus (HCV).

Algorithms↗
PubMed2001

[Patient records: supporting interprofessional communication in hospital].

Complete and continuous documentation in patient records is an important condition for adequate communication with patients, between the professions concerned and to ensure the quality of the following working steps in care provision. Part of a German research project concerning the interprofessional communication in hospital was therefore to analyse the use of the documentation system. 54 users were asked about practical aspects of their documentation system and 450 patient records were evaluated. The analysis focused on the medical and nursing documentation of admission, process and discharge. Deficits that need to be improved appeared first of all in the practical aspects of the documentation system, the flow of information between the professions, in specific gaps of medical and nursing admission, documentation of process and discharge. Quality management is asked to improve and develop the documentation in collaboration with the users and to consider specific problems when introducing computer based records.

Documentation↗
PubMed2001

[Multiperspective estimates on the probability of patient return to work following orthopaedic rehabilitation: findings and predictive relevance].

This article analyses various methods of predicting whether patients in orthopaedic rehabilitation will return to work. In this regard, items of patients, physicians in charge of rehabilitation and general practitioners have been collected and compared to working time lost due to illness. In total, 72 % of patients had successfully returned to work after one year. The patients whose reintegration could not be achieved could be identified best by asking if they believed that they would be in a position to work until the statutory retirement age (96 % identified) on the one hand and on the other hand by the physicians' estimate as to the degree the last gainful activity might be resumed (90 % identified). In this context, the criteria have to be laid down very restrictively in order to sufficiently filter out patients not likely to return to work. The patients likely to return to work are identified best by means of the following characteristics: lack of intention to retire early (96 % identified), planning to return to work directly after rehabilitation (88 % identified), and little working time lost due to illness prior to rehab (86 % identified). In general, a major percentage of patients not likely to return to work can be identified by these statements of patients and physicians. The statements of general practitioners are clearly less valuable for prediction and show only weak correlation with the respective statements of the physicians in charge of rehabilitation.

Adult↗
PubMed2001

[Living organ donation vs. cadaveric donation - study of liver transplanted children and their families].

There is only scarce information on the quality of life of child recipients of liver transplants and their families. Particularly children with a living related graft and their families never have been compared to children who received a cadaveric graft and their families. We investigated the following issues in our study: How do parents and children from participating families rate their strain, their quality of life and their relationships within their family? Do families with a living - related donor differ from those with a cadaveric donor? What do living donors and their partners think about the donation retrospectively? The study was conducted with 106 participants from 50 families (42 mothers, 40 fathers, and 24 children older than 6 years). In 20 of these families, a living transplantation had been performed. Participants were interviewed and asked to fill out several questionnaires. School-aged children with a liver transplant show good social integration among their peers and in school. The child's disease, however, has a great impact on the family. Family members show a reduction in social contact, and an increase in marital crises, and problematic relations amongst siblings. Families in which a cadaveric graft was performed, are less satisfied with life, and show more symptoms of exhaustion. Every family studied possessed or acquired - a high degree of internal or external coping resources. Living - related donors tried hard to obtain an understanding of the medical context. The partner, rather than the donor himself, feels anxious before the donation. The limited time available for the decision to donate is not perceived by the donors to be critical. Ten percent of living donors feel "a little" that their health is affected. The decision to donate is supported "strongly" or "very strongly" by the partners in 80 % of the cases. A possible strain on the child through the expectation of gratitude by the donor is stated by 20 %. All of the donors agree that if they were to be asked today, they would donate again, only one of the partners raised objections. In summary, as a retrospective pilot study, this study primarily generates hypotheses rather than testing them and helps to develop research tools for the field. Results suggest that a psychological support be made available both prior to and following the operation, not only for the children but also for their families, with particular attention to the partners of the living donors and the siblings of the affected children.

Adolescent↗
PubMed2001

Hepatitis C virus protease inhibitors: current progress and future challenges.

Hepatitis C is a predominantly chronic viral infection, affecting 1-3% of the world population. The causative agent, the hepatitis C virus (HCV), has a positive strand-RNA genome that is utilized, in infected cells, as an mRNA to drive the synthesis of a large polyprotein precursor. This precursor subsequently undergoes proteolytic maturation to generate all of the functional, both structural and nonstructural proteins necessary for viral replication and assembly. The proteolytic activity that is responsible for the generation of the mature viral polymerase as well as for most of the cleavages occurring in the nonstructural region of the polyprotein is expressed by the virus itself and is contained in its nonstructural protein 3 (NS3). Here, the N-terminal 180 amino acids form a chymotrypsin-like serine protease domain. Full activation of this protease is achieved only after complexation with another viral protein, the cofactor protein NS4A. Together, NS3 and NS4A form the active, heterodimeric serine protease that presently is the target of medicinal chemistry efforts aiming at the development of inhibitors with potential antiviral activity. We here review the recent progress in our understanding of the structure and function of the enzyme and in the development of selective and potent NS3 protease inhibitors.

Binding Sites↗
PubMed2000

Optimization of the P'-region of peptide inhibitors of hepatitis C virus NS3/4A protease.

Infection by Hepatitis C Virus (HCV) leads to a slowly progressing disease that over two decades can lead to liver cirrhosis or liver cancer. Currently, one of the most promising approaches to anti-HCV therapy is the development of inhibitors of the NS3/4A protease, which is essential for maturation of the viral polyprotein. Several substrate-derived inhibitors of NS3/4A have been described, all taking advantage of binding to the S subsite of the enzyme. Inspection of the S' subsite of NS3/4A shows binding pockets which might be exploited for inhibitor binding, but due to the fact that ground-state binding to the S' subsite is not used by the substrate, this does not represent a suitable starting point. We have now optimized S'-binding in the context of noncleavable decapeptides spanning P6-P4'. Binding was sequentially increased by introduction of the previously optimized P-region [Ingallinella et al. (1998) Biochemistry 37, 8906-8914], change of the P4' residue, and combinatorial optimization of positions P2'-P3'. The overall process led to an increase in binding of more than 3 orders of magnitude, with the best decapeptide showing IC(50) < 200 pM. The binding mode of the decapeptides described in the present work shares features with the binding mode of the natural substrates, together with novel interactions within the S' subsite. Therefore, these peptides may represent an entry point for a novel class of NS3 inhibitors.

Amino Acids↗
PubMed2000

Alpha-ketoacids are potent slow binding inhibitors of the hepatitis C virus NS3 protease.

The replication of the hepatitis C virus (HCV), an important human pathogen, crucially depends on the proteolytic maturation of a large viral polyprotein precursor. The viral nonstructural protein 3 (NS3) harbors a serine protease domain that plays a pivotal role in this process, being responsible for four out of the five cleavage events that occur in the nonstructural region of the HCV polyprotein. We here show that hexapeptide, tetrapeptide, and tripeptide alpha-ketoacids are potent, slow binding inhibitors of this enzyme. Their mechanism of inhibition involves the rapid formation of a noncovalent collision complex in a diffusion-limited, electrostatically driven association reaction followed by a slow isomerization step resulting in a very tight complex. pH dependence experiments point to the protonated catalytic His 57 as an important determinant for formation of the collision complex. K(i) values of the collision complexes vary between 3 nM and 18.5 microM and largely depend on contacts made by the peptide moiety of the inhibitors. Site-directed mutagenesis indicates that Lys 136 selectively participates in stabilization of the tight complex but not of the collision complex. A significant solvent isotope effect on the isomerization rate constant is suggestive of a chemical step being rate limiting for tight complex formation. The potency of these compounds is dominated by their slow dissociation rate constants, leading to complex half-lives of 11-48 h and overall K(i) values between 10 pM and 67 nM. The rate constants describing the formation and the dissociation of the tight complex are relatively independent of the peptide moiety and appear to predominantly reflect the intrinsic chemical reactivity of the ketoacid function.

Alanine↗
PubMed2000

Bone-muscle strength indices for the human lower leg.

This cross-sectional study is based on images from the lower leg as assessed by peripheral quantitative computer tomography (pQCT). Measurements were performed in 39 female and 38 male control subjects and 15 female professional volleyball players, all between 18 and 30 years of age. The images were obtained at shank levels of 4%, 14%, 33%, and 66% from the distal end. Bone and muscle cross-sectional areas, and the bones' density-weighted area moment of resistance and of inertia were assessed. From these, muscle-bone strength indices (MBSIs) were developed for compression (CI = 100. bone area/muscle area) and bending (BI = 100. bone area moment of resistance/muscle area/tibia length). Significant correlations between muscle cross-sectional area and bone were found at all section levels investigated. The strongest correlation for compression was observed in the sections at 14% (correlation coefficient r = 0.74), where 4.10 +/- 0.46 cm(2) bone, on average, was related to 100 cm(2) muscle. The compression index (CI) at the 14% level was independent of the tibia length. Interestingly, the 15 athletes had significantly greater CIs than the control subjects. This is most probably due to the greater tension development in the athletes. The highest correlation for bending was for anteroposterior bending at 33% of tibia length (r = 0.81), where the area moment of resistance, R, was on, average, 4.21 +/- 0.54 cm(3)/100 cm(2) muscle/m tibia length. Analysis of the bones' area moment of inertia showed that buckling is a possible cause of bending at the 33% and 66% levels, but not at the 14% level. No gender differences in MBSI were found. Likewise, age was without significant effect. The data show that bone architecture depends critically on muscle cross section and tension development. Moreover, bone geometry (e.g., the tibia length) influences the geometrical distribution of bone mineral, as it was found that long bones adapted to the same compressive strength are wider than short ones. We conclude that MBSIs offer a powerful diagnostic tool for bone disorders and may contribute to improving the treatment of bone metabolic and other diseases.

Absorptiometry, Photon↗
PubMed2000

[Partial inpatient oncologic rehabilitation--results of a model project].

Medical rehabilitation in Germany is traditionally performed primarily in the inpatient setting. It was not until recent years that model forms of outpatient offers were first tested. In this article we will present the results of a comparative evaluation of inpatient and outpatient/partially outpatient oncological rehabilitation measures. Within the framework of a retrospective questionnaire study, oncological rehabilitants from both settings will be compared with regard to questions concerning the process of participation, rehabilitative goals, oncological interventions and perceived outcome from the perspective of the patient. An overall result is that persons who were treated in the outpatient setting, when compared with those treated in the inpatient setting, show more congruency than discrepancy with regard to all of these key topics. The results will be discussed with respect to further development of the rehabilitative health care system.

Adult↗
PubMed2000

[Expectations, concerns and therapeutic goals of patients at the beginning of oncologic rehabilitation].

The study focuses on the outcome of oncological rehabilitation in the inpatient setting. An oncology-specific questionnaire for the measurement of individual therapy goals was developed within the perspective of a goal-oriented evaluation concept. The article focuses on the first time-point of measurement (beginning of the rehabilitation measure) within a longitudinal study. 407 patients were studied either directly following their initial hospital treatment or at a later time-point during the course of the cancer illness. The presentation of the results include firstly a description and analysis of the patients' medical and psychosocial situation (including variables such as the perceived state of health and quality of life), as well as individual rehabilitation goals formulated by the patients themselves. Moreover, an analysis is performed of the expectations, hopes and fears of patients at the beginning of an oncological rehabilitation measure in the inpatient setting. Subgroup analyses focus on the influence of sociodemographic and emotional variables on the patients' expectations and goals.

Adaptation, Psychological↗
PubMed2000

Interdependence of spatial and temporal coding in the auditory midbrain.

To date, most physiological studies that investigated binaural auditory processing have addressed the topic rather exclusively in the context of sound localization. However, there is strong psychophysical evidence that binaural processing serves more than only sound localization. This raises the question of how binaural processing of spatial cues interacts with cues important for feature detection. The temporal structure of a sound is one such feature important for sound recognition. As a first approach, we investigated the influence of binaural cues on temporal processing in the mammalian auditory system. Here, we present evidence that binaural cues, namely interaural intensity differences (IIDs), have profound effects on filter properties for stimulus periodicity of auditory midbrain neurons in the echolocating big brown bat, Eptesicus fuscus. Our data indicate that these effects are partially due to changes in strength and timing of binaural inhibitory inputs. We measured filter characteristics for the periodicity (modulation frequency) of sinusoidally frequency modulated sounds (SFM) under different binaural conditions. As criteria, we used 50% filter cutoff frequencies of modulation transfer functions based on discharge rate as well as synchronicity of discharge to the sound envelope. The binaural conditions were contralateral stimulation only, equal stimulation at both ears (IID = 0 dB), and more intense at the ipsilateral ear (IID = -20, -30 dB). In 32% of neurons, the range of modulation frequencies the neurons responded to changed considerably comparing monaural and binaural (IID =0) stimulation. Moreover, in approximately 50% of neurons the range of modulation frequencies was narrower when the ipsilateral ear was favored (IID = -20) compared with equal stimulation at both ears (IID = 0). In approximately 10% of the neurons synchronization differed when comparing different binaural cues. Blockade of the GABAergic or glycinergic inputs to the cells recorded from revealed that inhibitory inputs were at least partially responsible for the observed changes in SFM filtering. In 25% of the neurons, drug application abolished those changes. Experiments using electronically introduced interaural time differences showed that the strength of ipsilaterally evoked inhibition increased with increasing modulation frequencies in one third of the cells tested. Thus glycinergic and GABAergic inhibition is at least one source responsible for the observed interdependence of temporal structure of a sound and spatial cues.

Acoustic Stimulation↗
PubMed1999

Conformational changes in human hepatitis C virus NS3 protease upon binding of product-based inhibitors.

One of the most promising approaches to anti-hepatitis C virus drug discovery is the development of inhibitors of the virally encoded protease NS3. This chymotrypsin-like serine protease is essential for the maturation of the viral polyprotein, and processing requires complex formation between NS3 and its cofactor NS4A. Recently, we reported on the discovery of potent cleavage product-derived inhibitors [Ingallinella et al. (1998) Biochemistry 37, 8906-8914]. Here we study the interaction of these inhibitors with NS3 and the NS3/cofactor complex. Inhibitors bind NS3 according to an induced-fit mechanism. In the absence of cofactor different binding modes are apparent, while in the presence of cofactor all inhibitors show the same binding mode with a small rearrangement in the NS3 structure, as suggested by circular dichroism spectroscopy. These data are consistent with the hypothesis that NS4A complexation induces an NS3 structure that is already (but not entirely) preorganized for substrate binding not only for what concerns the S' site, as already suggested, but also for the S site. Inhibitor binding to the NS3/cofactor complex induces the stabilization of the enzyme structure as highlighted by limited proteolysis experiments. We envisage that this may occur through stabilization of the individual N-terminal and C-terminal domains where the cofactor and inhibitor, respectively, bind and subsequent tightening of the interdomain interaction in the ternary complex.

Amino Acid Sequence↗
PubMed1999

Structural characterization of the interactions of optimized product inhibitors with the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein by NMR and modelling studies.

The interactions of peptide inhibitors, obtained by the optimization of N-terminal cleavage products of natural substrates, with the protease of human hepatitis C virus (HCV) are characterized by NMR and modelling studies. The S-binding region of the enzyme and the bound conformation of the ligands are experimentally determined. The NMR data are then used as the experimental basis for modelling studies of the structure of the complex. The S-binding region involves the loop connecting strands E2 and F2, and appears shallow and solvent-exposed. The ligand binds in an extended conformation, forming an antiparallel beta-sheet with strand E2 of the protein, with the P1 carboxylate group in the oxyanion hole.

Amino Acid Sequence↗