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Biomedical subjects

K Krause

Publications and source records attributed to K Krause.

At least 19 recordsLinked to original sources
PubMed2004

Carotid body denervation alters ventilatory responses to ibotenic acid injections or focal acidosis in the medullary raphe.

Our aim was to determine the effects of carotid body denervation (CBD) on the ventilatory responses to focal acidosis and ibotenic acid (IA) injections into the medullary raphe area of awake, adult goats. Multiple microtubules were chronically implanted into the midline raphe area nuclei either before or after CBD. For up to 15 days after bilateral CBD, arterial PCO2 (PaCO2) (13.3 +/- 1.9 Torr) was increased (P < 0.001), and CO2 sensitivity (-53.0 +/- 6.4%) was decreased (P <0.001). Thereafter, resting PaCO2 and CO2 sensitivity returned (P <0.01) toward control, but PaCO2 remained elevated (4.8 +/- 1.9 Torr) and CO2 sensitivity reduced (-24.7 +/- 6.0%) > or =40 days after CBD. Focal acidosis (FA) at multiple medullary raphe area sites 23-44 days post-CBD with 50 or 80% CO(2) increased inspiratory flow (Vi), tidal volume (Vt), metabolic rate (VO2), and heart rate (HR) (P <0.05). The effects of FA with 50% CO2 after CBD did not differ from intact goats. However, CBD attenuated (P <0.05) the increase in Vi, Vt, and HR with 80% CO2, but it had no effect on the increase in VO2. Rostral but not caudal raphe area IA injections increased Vi, BP, and HR (P < 0.05), and these responses were accentuated (P <0.001) after CBD. CO2 sensitivity was attenuated (-20%; P <0.05) <7 days after IA injection, but thereafter it returned to prelesion values in CBD goats. We conclude the following: 1) the attenuated response to FA after CBD provides further evidence that the carotid bodies provide a tonic facilitory input into respiratory control centers, 2) the plasticity after CBD is not due to increased raphe chemoreceptor sensitivity, and 3) the "error-sensing" function of the carotid body blunts the effect of strong stimulation of the raphe.

Acidosis↗
PubMed2004

[Münster age- and retina study (MARS). Association between risk factors for arteriosclerosis and age-related macular degeneration].

BACKGROUND: The association between arteriosclerosis and age-related macular degeneration (AMD) has only been examined in a few studies and the data is still very inconsistent. METHODS: A cross sectional study was initiated with 730 patients from the Münster age and retina study (MARS) which examines patients in the age range 60 to 80 years old who were referred by ophthalmologists from the Muenster area. Patients with narrow angle glaucoma were excluded. All patients underwent a standardized ophthalmoscopic examination und were classified into four groups: group 1 without AMD ( n=190), group 2 with unilateral or bilateral early forms of AMD ( n=340), group 3 with unilateral late forms of AMD ( n=139) and group 4 with bilateral late forms of AMD ( n=50). By means of these groups it was tested if there was a significant difference between the different risk factors for arteriosclerosis. RESULTS: The mean age was 72 years and 58% were women and the sex distribution within the different groups did not differ significantly (all trend tests with p>0.1). General risk factors for arteriosclerosis such as diabetes, body-mass-index and hypertension did not differ significantly (all trend tests with p>0.1). The number of smokers increased significantly with the severity of AMD ( p=0.02). Furthermore, various lipids were examined, adjusted for age and sex and showed significant decrease of HDL ( p=0.087) and significant increases of the HDL/LDL quotient ( p=0.0007) and the non-sober triglyceride values ( p=0.0058) correlated with the severity of AMD. CONCLUSIONS: There was a highly significant, direct association of indicators of dyslipidemia such as increasing HDL/LDL quotient and decreasing HDL with the severity of AMD. These results were underlined by increased triglyceride levels even if they were taken non-sober. The results must be interpreted with caution due to the explorative character of the evaluation.

Age Distribution↗
PubMed2002

Model structure identification for wastewater treatment simulation based on computational fluid dynamics.

The objective of this presented project is to use the results of an CFD simulation to automatically, systematically and reliably generate an appropriate model structure for simulation of the biological processes using CSTR activated sludge compartments. Models and dynamic simulation have become important tools for research but also increasingly for the design and optimisation of wastewater treatment plants. Besides the biological models several cases are reported about the application of computational fluid dynamics ICFD) to wastewater treatment plants. One aim of the presented method to derive model structures from CFD results is to exclude the influence of empirical structure selection to the result of dynamic simulations studies of WWTPs. The second application of the approach developed is the analysis of badly performing treatment plants where the suspicion arises that bad flow behaviour such as short cut flows is part of the problem. The method suggested requires as the first step the calculation of fluid dynamics of the biological treatment step at different loading situations by use of 3-dimensional CFD simulation. The result of this information is used to generate a suitable model structure for conventional dynamic simulation of the treatment plant by use of a number of CSTR modules with a pattern of exchange flows between the tanks automatically. The method is explained in detail and the application to the WWTP Wuppertal Buchenhofen is presented.

Algorithms↗
PubMed2002

Simulation of a nitrification control concept considering influent ammonium load.

Buchenhofen wastewater treatment plant of Wupperverband (650,000 p.e.) is currently being expanded for targeted nitrogen elimination. In view of the limited space available for extension, an optimized control concept is to be used in order to minimize the number of additional tanks required. This concept was investigated by dynamic simulation based on Activated Sludge Model No. 1. The investigations included a pure feedback control configuration and a configuration combining feedback und feedforward control, considering the influent ammonium load, for aeration. The results show that combined feedforward/feedback control has significant advantages over pure feedback control. In particular, this configuration allows a reduction in the effluent NH4-N peaks, which is especially important because of the low NH4-N limit of 5 mg NH4-N/L in a grab sample.

Computer Simulation↗
PubMed2001

Expression of the cell cycle phosphatase cdc25C is down-regulated by the tumor suppressor protein p53 but not by p73.

The cdc25C phosphatase dephosphorylates cdc2 kinase which then in complex with cyclin B can catalyse transition from the G(2) phase to mitosis. We demonstrate that transcription of cdc25C is repressed by p53 in a dose-dependent manner. In stably transfected DLD-1 colorectal adenocarcinoma cells, cdc25C expression is down-regulated when p53 is induced from a (tet)-off-regulated system. In contrast to p53, its homologue p73 is not able to down-modulate cdc25C expression. A previously identified site in the cdc25C promoter can bind p53 in vitro and, when placed in a heterologous construct, is able to activate transcription. However, transcriptional repression by p53 is not mediated through this site but is dependent on a segment containing three CCAAT-boxes. In general down-regulation of cdc25C transcription by reducing the levels of active cdc2 kinase contributes to G(2) arrest and G(2)/M checkpoint control. This reveals functional differences between p73 and p53 in regulating cell division.

Animals↗
PubMed2001

A stress-responsive glyoxalase I from the parasitic nematode Onchocerca volvulus.

Glyoxal, methylglyoxal and other physiological alpha-oxoaldehydes are formed by the lipid peroxidation, glycation and degradation of glycolytic intermediates. They are detoxified enzymically by the glyoxalase system. To investigate the physiological function of glyoxalase I in parasitic organisms, the cDNA for glyoxalase I from the filarial nematode Onchocerca volvulus (designated Ov-GloI) has been cloned and characterized. The isolated cDNA contains an open reading frame of 579 bp encoding a protein with a calculated molecular mass of 21930 Da. Owing to the high degree of sequence identity (60%) with human glyoxalase I, for which the X-ray structure is available, it has been possible to build a three-dimensional model of Ov-GloI. The modelled core of Ov-GloI is conserved compared with the human glyoxalase I; however, there are critical differences in the residues lining the hydrophobic substrate-binding pocket of Ov-GloI. A 22 kDa protein was obtained by heterologous expression in Escherichia coli. A homogeneous enzyme preparation was obtained by affinity purification and functional characterization of the recombinant enzyme included the determination of kinetic constants for methylglyoxal and phenylglyoxal as well as inhibition studies. Gel filtration demonstrated a dimeric structure. To assess the role of Ov-GloI as a potential vaccine candidate or serodiagnostic tool, the serological reactivity of the recombinant Ov-GloI was analysed with sera from microfilaria carriers and specific IgG1 antibodies were detected. The effects of oxidative insult, namely plumbagin and xanthine/xanthine oxidase, on the gene transcript level of Ov-GloI were investigated. By using a semi-quantitative PCR ELISA it was shown that Ov-GloI is expressed at elevated levels under conditions of oxidative stress.

Amino Acid Sequence↗
PubMed2001

Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis.

Immunocompromised patients are at risk of developing toxoplasma encephalitis (TE). Standard therapy regimens (including sulfadiazine plus pyrimethamine) are hampered by severe side effects. While atovaquone has potent in vitro activity against Toxoplasma gondii, it is poorly absorbed after oral administration and shows poor therapeutic efficacy against TE. To overcome the low absorption of atovaquone, we prepared atovaquone nanosuspensions (ANSs) for intravenous (i.v.) administration. At concentrations higher than 1.0 microg/ml, ANS did not exert cytotoxicity and was as effective as free atovaquone (i.e., atovaquone suspended in medium) against T. gondii in freshly isolated peritoneal macrophages. In a new murine model of TE that closely mimics reactivated toxoplasmosis in immunocompromised hosts, using mice with a targeted mutation in the gene encoding the interferon consensus sequence binding protein, i.v.-administered ANS doses of 10.0 mg/kg of body weight protected the animals against development of TE and death. Atovaquone was detectable in the sera, brains, livers, and lungs of mice by high-performance liquid chromatography. Development of TE and mortality in mice treated with 1.0- or 0.1-mg/kg i.v. doses of ANS did not differ from that in mice treated orally with 100 mg of atovaquone/kg. In conclusion, i.v. ANSs may prove to be an effective treatment alternative for patients with TE.

Animals↗
PubMed2001

A telephone needs assessment for potential high utilizers.

BACKGROUND AND OBJECTIVES: We conducted a telephone needs assessment of patients at risk for high utilization of health services to determine the type of intervention that might be most responsive to their needs. METHODS: Family practice patients who were classified as at high risk based on self-reported health-related quality of life (HRQOL), age, and gender received a structured telephone interview to ask about their health problems, difficulties with their health care, and types of help programs that might be useful to them. RESULTS: Of 867 adult patients randomly selected as eligible for the study, 352 completed the Duke Health Profile to measure HRQOL, 122 were classified at risk for high utilization, and 104 were interviewed by telephone. Patient-reported health problems were similar to provider-reported problems. High-risk patients reported difficulties receiving help from the clinic on issues of communication and logistics (43.9%), limitations of clinic facilities and services (26.3%), and financial concerns (26.3%). Of the highest risk patients, 45.8% expressed willingness to participate in help programs conducted over the telephone. CONCLUSIONS: Many high-risk patients might benefit from participation in a telephone intervention program. A future study is needed to measure the effectiveness of such a program to improve utilization of health services.

Adult↗
PubMed2000

NF-Y mediates the transcriptional inhibition of the cyclin B1, cyclin B2, and cdc25C promoters upon induced G2 arrest.

During normal cell cycles, the function of mitotic cyclin-cdk1 complexes, as well as of cdc25C phosphatase, is required for G2 phase progression. Accordingly, the G2 arrest induced by DNA damage is associated with a down-regulation of mitotic cyclins, cdk1, and cdc25C phosphatase expression. We found that the promoter activity of these genes is repressed in the G2 arrest induced by DNA damage. We asked whether the CCAAT-binding NF-Y modulates mitotic cyclins, cdk1, and cdc25C gene transcription during this type of G2 arrest. In our experimental conditions, the integrity of the CCAAT boxes of cyclin B1, cyclin B2, and cdc25C promoters, as well as the presence of a functional NF-Y complex, is strictly required for the transcriptional inhibition of these promoters. Furthermore, a dominant-negative p53 protein, impairing doxorubicin-induced G2 arrest, prevents transcriptional down-regulation of the mitotic cyclins, cdk1, and cdc25C genes. We conclude that, as already demonstrated for cdk1, NF-Y mediates the transcriptional inhibition of the mitotic cyclins and the cdc25C genes during p53-dependent G2 arrest induced by DNA damage. These data suggest a transcriptional regulatory role of NF-Y in the G2 checkpoint after DNA damage.

CCAAT-Binding Factor↗
PubMed2000

The tumour suppressor protein p53 can repress transcription of cyclin B.

The tumour suppressor protein p53 has functions in controlling the G(1)/S and G(2)/M transitions. Central regulators for progression from G(2) to mitosis are B-type cyclins complexed with cdc2 kinase. In mammals two cyclin B proteins are found, cyclin B1 and B2. We show that upon treatment of HepG2 cells with 5-fluorouracil or methotrexate, p53 levels increase while concentrations of cyclin B2 mRNA, measured by RT-PCR with the LightCycler system, are reduced. In DLD-1 colorectal adenocarcinoma cells (DLD-1-tet-off-p53) cyclin B1 and B2 mRNA levels drop after expression of wild-type p53 but not after induction of a DNA binding-deficient mutant of p53. Analysis of the cyclin B2 promoter reveals specific repression of this gene by p53. Transfection of wild-type p53 into SaOS-2 cells shuts off transcription from a cyclin B2 promoter-luciferase construct whereas a p53 mutant protein does not. The cyclin B2 promoter does not contain a consensus p53 binding site. Most of the p53-dependent transcriptional responsiveness resides in its 226 bp core promoter. Taken together with earlier observations on p53-dependent transcription of cyclin B1, our results suggest that one way of regulating G(2) arrest may be a reduction in cyclin B levels through p53-dependent transcriptional repression.

Cyclin B↗
PubMed2000

Activated K-ras is involved in regulation of integrin expression in human colon carcinoma cells.

Integrins participate in controlling proliferation and migration. Therefore, changes in integrin expression might be responsible for unrestrained proliferation and invasiveness of tumor cells. Alterations of integrin subunit expression have been observed in human colon carcinoma, especially loss or reduction of the alpha5 subunit, which was observed consistently. The mechanisms responsible for reduction of alpha5 expression and alteration of expression of other integrins are not fully understood. Circumstantial evidence from previous investigations points to an involvement of activated ras oncogenes in repression of integrin expression. The K-ras protooncogene is activated by point mutation in 50% of human colon carcinomas. Thus, we choose an antisense approach for specific inactivation of activated K-ras in the human colon carcinoma cell line SW 480 in order to test whether activated K-ras contributes to changes in integrin expression on colon carcinoma cells. Cell surface expression of the alpha1 and the alpha5 subunit was increased in K-ras antisense transfected clones, cell surface expression of the alpha3 subunit and the alphav subunit was decreased. This shows, in a human system, that activated K-ras is involved in diminishing cell surface expression of the alpha1beta1 collagen/laminin receptor and the alpha5beta1 fibronectin receptor, both of which are implicated in maintenance of a non-transformed phenotype. Moreover, activated K-ras contributes to increased cell surface expression of the alpha3beta1 laminin/collagen/fibronectin receptor and the alphavbeta5 vitronectin receptor, which might play a role in metastatic behavior of tumor cells.

Adenocarcinoma↗
PubMed2000

Disruption of plastid-encoded RNA polymerase genes in tobacco: expression of only a distinct set of genes is not based on selective transcription of the plastid chromosome.

Plastids of higher plants operate with at least two distinct DNA-dependent RNA polymerases, which are encoded in the organelle (PEP) and in the nucleus (NEP), respectively. Plastid run-on assays and Northern analyses were employed to analyse gene expression in tobacco mutant plastids lacking the PEP genes rpoA, rpoB or rpoC1. Hybridisation of run-on transcripts to restriction fragments representing the entire tobacco plastid chromosome, as well as to selected plastid gene-specific probes, shows that all parts of the plastid DNA are transcribed in rpo-deficient plastids. In comparison to wild-type chloroplasts, which are characterized by preferential transcription of photosynthesis-related genes in the light, mutant plastids exhibit a different transcription pattern with less pronounced differences in the hybridisation intensities between the individual genes. The analysis of steady-state transcript patterns and transcription rates of selected genes in both types of plastids demonstrates that differences in transcription rates are not necessarily paralleled by corresponding changes in transcript levels. The accumulation of large transcripts in the mutant plastids indicates that processing of primary transcripts may be impaired in the absence of PEP. These data suggest that, contrary to the prevailing view, much of the regulation of NEP-driven plastid gene expression in the rpo-deficient mutants is not based on differential promoter usage but is exerted at post-transcriptional levels.

Chloroplasts↗
PubMed2000

Molecular, functional and ultrastructural characterisation of plastids from six species of the parasitic flowering plant genus Cuscuta.

Plastids of Cuscuta reflexa Roxb., C. subinclusa D. et H., C. gronovii Willd. and C. campestris Yunck. possess thylakoids and contain both chlorophyll a and b in a ratio similar to that of stem tissue of the systematically closely related but 'normal' green Ipomoea tricolor. In contrast, plastids of C. odorata R. et P. and C. grandiflora H.B.K. do not contain any chlorophyll or possess thylakoids. Light-driven electron transport, as measured by oxygen evolution and indicated by analysis of chlorophyll fluorescence, was present in all chlorophyll-containing species. The photosystem II efficiency was low and ranged from 0.511 to 0.687. The plastid rbcL gene could not be detected in C. odorata, but was present in all other tested species. Neither rbcL transcripts nor the large subunit of ribulose-1,5-bisphosphate carboxylase-oxygenase (Rubisco) could be detected in C. odorata and C. grandiflora. Low amounts of the large subunit of Rubisco were detected immunologically in all other Cuscuta species. Apparently, the genus Cuscuta comprises species with different degrees of plastid functionality, ranging from intact chloroplasts, via plastids with impaired protein production and gene expression to plastids with reduced plastome gene content.

Blotting, Northern↗
PubMed2000

Conformational properties of a cyclic peptide bradykinin B2 receptor antagonist using experimental and theoretical methods.

The solution conformation of the cyclic peptide J324 (cyclo0,6-[Lys0,Glu6,D-Phe7]BK), an antagonist targeted at the bradykinin (BK) B2 receptor, has been investigated using experimental and theoretical methods. In order to gain insight into the structural requirements essential for BK antagonism, we carried out molecular dynamics (MD) simulations using simulated annealing as the sampling protocol. Following a free MD simulation we performed simulations using nuclear Overhauser enhancement (NOE) distance constraints determined by NMR experiments. The low-energy structures obtained were compared with each other, grouped into families and analyzed with respect to the presence of secondary structural elements in their backbone. We also introduced new ways of plotting structural data for a more comprehensive analysis of large conformational sets. Finally, the relationship between characteristic backbone conformations and the spatial arrangement of specific pharmacophore centers was investigated.

Bradykinin Receptor Antagonists↗
PubMed1999

Expression of p73 and its relation to histopathology and prognosis in hepatocellular carcinoma.

BACKGROUND: The protein p73, the first identified homologue of the tumor suppressor gene p53 (also known as TP53), has been shown to induce apoptosis (programmed cell death), but its function in tumor development has not been established. This study was undertaken to investigate the expression of p73 in liver tissue of patients with hepatocellular carcinoma (HCC) and to determine whether this expression has any impact on prognosis. METHODS: In situ hybridization and immunohistochemistry for the detection of p73 RNA transcripts and protein, respectively, were performed in tissues from 193 patients with curatively (R0-) resected HCC. Patients receiving liver transplantation were excluded. The results obtained were analyzed with respect to their association with pathohistologic stage, Edmondson grade, p53 expression status and several histopathologic factors of possible prognostic value, and, finally, with patient survival. RESULTS: RNA transcripts encoding p73 were detected by in situ hybridization in tumor cells but not in stromal, endothelial, or inflammatory cells or in cholangiocytes. Transcripts were also found occasionally in non-neoplastic hepatocytes. By immunohistochemistry, we detected p73 protein in 61 (32%) of the 193 carcinomas examined. Positive immunohistochemical staining was confined to the cell nucleus. Univariate survival analysis showed that p73 expression status was statistically significantly related to prognosis (two-sided P<.0001). Patients with p73-positive tumors had a poorer prognosis than those with p73-negative carcinomas. Multivariate Cox survival analysis identified the age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. CONCLUSION: The protein p73 is overexpressed by a subset of HCCs and could serve as a useful indicator of prognosis in patients with this disease.

Apoptosis↗