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Biomedical subjects

K Engel

Publications and source records attributed to K Engel.

At least 19 recordsLinked to original sources
PubMed2002

Plasma glutamine and glutamate concentrations in Gabonese children with Plasmodium falciparum infection.

BACKGROUND: Low plasma glutamine levels in critical illness, neonates and burns patients are associated with poor outcome and increased risk of intercurrent infection. AIM: To investigate the relationship between plasma glutamine/glutamate levels and severity/outcome of malaria. DESIGN: Two-hospital prospective study, with both febrile and healthy controls. METHODS: We measured plasma glutamine and glutamate concentrations in 239 Gabonese patients: 145 children with malaria (86 with severe, 36 with moderate and 23 with uncomplicated disease), 42 healthy children, 44 febrile controls and eight healthy adults, and related findings to conventional markers of disease severity such as plasma lactate. RESULTS: Median (IQR) plasma glutamine was lower in uncomplicated falciparum malaria and in moderate malaria than in healthy controls: 353 (287-474) and 379 (293-448) vs. 485 (428-531) micromol/l, respectively; p<0.01 for both malaria groups vs. controls. In contrast, plasma glutamine was within the normal range in those with severe malaria and in febrile control children: 431 (342-525) and 472 (338-547) micromol/l, respectively. Furthermore, plasma glutamine was significantly higher in the children who died with malaria than in survivors: 514 (374-813) (n=12) vs. 399 (316-475) micromol/l (n=133), respectively; p=0.001. There were no significant differences in plasma glutamate concentrations between any of the study groups. DISCUSSION: In severe malaria, there was a positive correlation between plasma glutamine and lactate levels (p=0.009, r=0.281). This correlation may reflect impaired gluconeogenesis. Glutamine supplementation is probably not justified in severe P. falciparum infection.

Biomarkers↗
PubMed2001

Securing interoperability between chip card based medical information systems and health networks.

Health information systems supporting shared care are going to be distributed and interoperable. Dealing with sensitive personal medical information, such information systems have to provide appropriate security services, allowing only authorised users restricted access rights to the patients' data according to the 'need to know' principle. Especially in healthcare, chip card based information systems occur in the shape of patient data cards providing informational self determination and mobility of the users as well as quality, integrity, accountability, and availability of the data stored on the card, thus improving the shared care of patients. The DIABCARD project aims at the implementation and evaluation of a chip card based medical information system (CCMIS) for facilitating communication and co-operation between health professionals in different organisations or departments caring the same patient with diabetes as an example. In co-operation with the EC-funded TrustHealth(2) project, communication and application security services needed are provided like strong authentication as well as the derived services such as authorisation, access control, accountability, confidentiality, etc. The solution is based on Health Professional Cards and Trusted Third Party services. In addition to the secure handling of the patient's chip card and data in DIABCARD workstations, the secure communication between these workstations and related departmental systems has been implemented. Based on the results of this feasibility study, an enhanced security services specification for the DIABCARD example of a CCMIS is provided which will be implemented in the framework of a health network being established in the German federal state Bavaria. Beside the preferred solution of a combination of Patient Identification Card and Patient Data Card, lower level alternatives using card-verifiable certificates are explained in some details. Finally, a few legal issues, future trends like the XML standard set and their implications for the solution presented as well as for distributed health information systems in general are shortly discussed.

Computer Security↗
PubMed2001

Expression of the gap junction connexins Cx43, Cx45 and Cx26 in human uterine leiomyomata.

Uterine leiomyomata of 34 premenopausal women undergoing leiomyomectomy or hysterectomy, and in four cases the corresponding myometrium, were collected at laparotomy or laparoscopy to investigate the ability of these benign smooth muscle cell tumors to express different connexins. Immunohistochemical and Northern blot analyses were performed for the characterization of the expression of connexins Cx43, Cx45, Cx26 and Cx32. Immunofluorescence revealed the presence of Cx43 in most leiomyomata. Only seven leiomyomata lacked Cx43 expression. Cx45 was expressed in 13, a weak Cx26 immunostaining was found in seven cases, whereas Cx32 could not be detected. No correlations between the 17 beta-estradiol or progesterone serum levels and the expression patterns of the connexins Cx43, Cx45 and Cx26 could be observed. Gonadotropin-releasing hormone (GnRH)-agonist or progestin treatment did not influence the connexin expression pattern. Northern blot analyses confirmed these results; however, transcripts of Cx26 were not detectable. Connexin transcripts between myomata and the corresponding myometrium showed no obvious differences. Our data show that uterine leiomyomata are capable of expressing different connexins comparable to the corresponding myometrium, but do not respond to different hormonal conditions. The ability to express the appropriate connexins could explain why these tumors, though developing independently of hormonal levels, are still differentiated benign smooth muscle tumors.

Blotting, Northern↗
PubMed2001

Comparison of methods for the rapid laboratory assessment of children with malaria.

Rapid diagnosis and accurate quantification of Plasmodium falciparum parasitemia are important for the management of malaria. The assessment of disease severity also depends on evaluation of metabolic indexes such as blood glucose and lactate concentrations. Here we describe an accurate and rapid alternative to conventional thick film examination (Lambaréné method). We also assess near-patient methods for measuring blood glucose (OneTouch) and lactate (Accusport). The accuracy of the Lambaréné method is similar to that of thin films. Results from the OneTouch glucose meter also are in good agreement with a YSI 2300 reference meter. Overall, the Accusport lactate meter agrees poorly with the YSI 2300 reference meter. However, the sensitivity and specificity to detect hyperlactatemia (blood lactate > or = 5 mmol/L) are 0.94 and 0.98, respectively.

Blood Glucose↗
PubMed2001

Enhanced security services for enabling pan-European healthcare networks.

Establishing the Shared Care environment, communication and co-operation between healthcare establishments involved must be provided in a trustworthy way. This challenge is even more important for health networks using the Internet. In that context, services assuring both communication security and application security must be provided. Especially in the e-health environment, additionally to identity-related services certifying data or properties of principals, trustworthiness or authorisation for objects, components and functions must be established by Trusted Third Parties (TTP). Within the European Commission's Information Society Technologies (IST) Programme, the HARP project provides the "HARP Cross-Security Platform (HCSP)" needed in the open Web environment of pan-European networks. The solutions are under implementation and evaluation in the German ONCONET enabling a trustworthy framework for both health professionals and patients as well as supporting clinical studies.

Computer Security↗
PubMed2000

E- and P-selectin expression in endometriotic tissues and the corresponding endometria.

Endometriosis is one of the most frequent diseases in gynecology. It is histologically defined as a non-malignant pathology in which endometrial-like tissue is found outside the uterus. The pathogenesis and mechanisms involved in the development of endometriosis-associated pain symptoms are still under investigation. A local peritoneal inflammation seems to play an important role in the origin of these symptoms. Selectins belong to a group of cell adhesion molecules that mediate the localization of circulating leukocytes on the endothelium at the sites of inflammation. The aim of this study was to investigate the expression of E- and P-selectins in endometriotic tissues and the corresponding endometria. Thirty endometriotic samples, 13 corresponding endometria and six endometria of patients without endometriosis were analyzed using an immunohistochemical technique. Just two endometriotic tissues expressed E-selectin, while five samples were positive for P-selectin. The selectin expression of the corresponding endometria was also very weak. No correlations between the revised American Fertility Society (rAFS) score or the hormonal situation of the patients at the time of biopsy and the selectin expression could be found. In conclusion, the selectin expression in endometriotic glands does not play an important role in the initiation of inflammatory processes caused by endometriosis. This inflammation must be considered as a secondary reaction after the implantation of the endometriotic glands, so that endometriotic tissues are not able to induce, by the expression of selectins, a direct inflammation.

Biopsy↗
PubMed2000

Secure interoperability of patient data cards in health networks.

In the healthcare area, chip card based information systems occur in the shape of patient data cards providing informational self determination and mobility of the users as well as quality, integrity, accountability, and availability of the data stored on the card, thus improving the shared care of patients. Dealing with sensitive personal medical information, shared care information systems have to provide appropriate security services, only authorized users allowing restricted rights to the patients' data according to the "need to know" principle. The DIABCARD project aims the implementation and evaluation of a chip card based medical information system (CCMIS) for facilitating communication and co-operation between health professionals in different organisations or departments caring the same patient with Diabetes as an example. In co-operation with the EC-funded TrustHealth project, the communication and application security services needed are provided as strong authentication and the derived services like authorization, access control, accountability, confidentiality etc. The solution is based on Health Professional Cards and Trusted Third Party services. Besides the secure handling of the patient's chip cart in DIABCARD workstations, also the secure communication between these workstations and related departmental systems has been implemented. Finally, a few legal issues, future trends like the XML standard set and their implications for the solution presented as well as for distributed health information systems in general are shortly discussed.

Computer Communication Networks↗
PubMed1999

MAPKAP kinase 2 phosphorylates serum response factor in vitro and in vivo.

Several growth factor- and calcium-regulated kinases such as pp90(rsk) or CaM kinase IV can phosphorylate the transcription factor serum response factor (SRF) at serine 103 (Ser-103). However, it is unknown whether stress-regulated kinases can also phosphorylate SRF. We show that treatment of cells with anisomycin, arsenite, sodium fluoride, or tetrafluoroaluminate induces phosphorylation of SRF at Ser-103 in both HeLa and NIH3T3 cells. This phosphorylation is dependent on the kinase p38/SAPK2 and correlates with the activation of MAPKAP kinase 2 (MK2). MK2 phosphorylates SRF in vitro at Ser-103 with similar efficiency as the small heat shock protein Hsp25 and significantly better than CREB. Comparison of wild type murine fibroblasts with those derived from MK2-deficient mice (Mk(-/-)) reveals MK2 as the major SRF kinase induced by arsenite. These results demonstrate that SRF is targeted by several signal transduction pathways within cells and establishes SRF as a nuclear target for MAPKAP kinase 2.

3T3 Cells↗
PubMed1999

Communication security in open health care networks.

Fulfilling the shared care paradigm, health care networks providing open systems' interoperability in health care are needed. Such communicating and co-operating health information systems, dealing with sensitive personal medical information across organisational, regional, national or even international boundaries, require appropriate security solutions. Based on the generic security model, within the European MEDSEC project an open approach for secure EDI like HL7, EDIFACT, XDT or XML has been developed. The consideration includes both securing the message in an unsecure network and the transport of the unprotected information via secure channels (SSL, TLS etc.). Regarding EDI, an open and widely usable security solution has been specified and practically implemented for the examples of secure mailing and secure file transfer (FTP) via wrapping the sensitive information expressed by the corresponding protocols. The results are currently prepared for standardisation.

Computer Communication Networks↗
PubMed1998

Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation.

UNLABELLED: To study the intracellular localization of MAPKAP kinase 2 (MK2), which carries a putative bipartite nuclear localization signal (NLS), we constructed a green fluorescent protein-MAPKAP kinase 2 fusion protein (GFP-MK2). In transfected cells, this protein is located predominantly in the nucleus; unexpectedly, upon stress, it rapidly translocates to the cytoplasm. This translocation can be blocked by the p38 MAP kinase inhibitor SB203580, indicating its regulation by phosphorylation. Molecular mimicry of MK2 phosphorylation at T317 in GFP-MK2 led to a mutant which is located almost exclusively in the cytoplasm of the cell, whereas the mutant T317A shows no stress-induced redistribution. Since leptomycin B, which inhibits the interaction of exportin 1 with the Rev-type leucine-rich nuclear export signal (NES), blocks stress-dependent translocation of GFP-MK2, it is supposed that phosphorylation-induced export of the protein causes the translocation. We have identified the region responsible for nuclear export in MK2 which is partially overlapping with and C-terminal to the autoinhibitory motif. This region contains a cluster of hydrophobic amino acids in the characteristic spacing of a leucine-rich Rev-type NES which is necessary to direct GFP-MK2 to the cytoplasm. However, unlike the Rev-type NES, this region alone is not sufficient for nuclear export. The data obtained indicate that MK2 contains a constitutively active NLS and a stress-regulated signal for nuclear export. KEYWORDS: nuclear export/nuclear import/protein phosphorylation/signal transduction/stress response

3T3 Cells↗
PubMed1997

CREB is activated by UVC through a p38/HOG-1-dependent protein kinase.

Changes in environmental conditions such as the addition of growth factors or irradiation of cells in culture first affect immediate response genes. We have shown previously that short wavelength UV irradiation (UVC) elicits massive activation of several growth factor receptor-dependent pathways. At the level of the immediate response gene c-fos, these pathways activate the transcription factor complex serum response factor (SRF)-p62TCF which mediates part of the UV-induced transcriptional response. These studies have, however, suggested that more that one pathway is required for full UV responsiveness of c-fos. Using appropriate promoter mutations and dominant-negative cAMP response element (CRE)-binding protein (CREB), we now find that UVC-induced transcriptional activation depends also on the CRE at position -60 of the c-fos promoter and on the functionality of a CREB. Upon UV irradiation, CREB and ATF-1 are phosphorylated at serines 133 and 63, respectively, preceded by and dependent on activation of p38/RK/HOG-1 and of a p38/RK/HOG-1-dependent p108 CREB kinase. Although p90RSK1 and MAPKAP kinase 2 are also activated by UV, p90RSK1 does not, at least not decisively, participate in this signalling pathway to CREB and ATF-1 as it is not p38/RK/HOG-1 dependent, and CREB is a poor substrate for MAPKAP kinase 2 in vitro. On the basis of resistance to the growth factor receptor inhibitor suramin and of several types of cross-refractoriness experiments, the UVC-induced CREB/ATF-1 phosphorylation represents an as yet unrecognized route of UVC-induced signal transduction, independent of suramin-inhibitable growth factor receptors and different from the Erk 1,2-p62TCF pathway.

Activating Transcription Factor 1↗
PubMed1997

PMA-induced activation of the p42/44ERK- and p38RK-MAP kinase cascades in HL-60 cells is PKC dependent but not essential for differentiation to the macrophage-like phenotype.

The signaling mechanisms leading to phorbol ester myristate (PMA)-induced differentiation of HL-60 cells to the macrophagelike phenotype were investigated by using different protein kinase inhibitors. The protein kinase C inhibitor Ro 31-8220 specifically blocks PMA-induced differentiation, activation of the p42/44ERK- and p38RK-MAP kinase cascades and Hsp27-phosphorylation in HL-60 cells. Because Ro 31-8220 does not inhibit activation of the MAP kinase cascades by protein kinase C (PKC)-independent signals such as epidermal growth factor (EGF), heat shock, or anisomycin in these cells, only PMA-induced activation of the MAP kinases can be downstream of PKC. The MEK1 inhibitor PD 098059 and the p38RK inhibitor SB 203580 also were used to analyze whether the PMA-induced PKC-dependent activation of MAP kinases is involved in the differentiation process. Under certain conditions, PD 098059 can completely block the PMA-induced activation of the p42ERK as monitored by immunoprecipitation kinase assay by using the substrate myelin basic protein. SB 203580 specifically inhibits activation of p38RK as judged by MAPKAP kinase 2 activity against the substrate Hsp27 and also blocks Hsp27 phosphorylation in the cells. In contrast, neither PD 098059 nor SB 203580 nor both inhibitors together prevent PMA-induced differentiation of the HL-60 cells to the macrophagelike phenotype. The results suggest the existence of a diversification of PMA-induced signaling in HL-60 cells downstream of PKC, leading to activation of MAP kinases that are not essential for differentiation and to phosphorylation of other, so far unidentified, targets responsible for differentiation.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1997

The protein kinase inhibitor SB203580 uncouples PMA-induced differentiation of HL-60 cells from phosphorylation of Hsp27.

HL-60 cells are an attractive model for studies of human myeloid cell differentiation. Among the well-examined parameters correlated to differentiation of HL-60 cells are the expression and phosphorylation of the small heat shock protein Hsp27. Here we demonstrate that PMA treatment of HL-60 cells stimulates different MAP kinase cascades, leading to significant activation of ERK2 and p38 reactivating kinase (p38RK). Using the protein kinase inhibitor SB 203580, we specifically inhibited p38RK and, thereby, activation of its target MAP kinase-activated protein kinase 2 (MAPKAP kinase 2), which is the major enzyme responsible for small Hsp phosphorylation. As a result, PMA-induced Hsp27 phosphorylation is inhibited in SB 203580-treated HL-60 cells indicating that p38RK and MAPKAP kinase 2 are components of the PMA-induced signal transduction pathway leading to Hsp27 phosphorylation. We further demonstrate that, although PMA-induced phosphorylation is inhibited, SB 203580-treated HL-60 cells are still able to differentiate to the macrophage-like phenotype as judged by decrease in cell proliferation, induction of expression of the cell surface antigen CD11b and changes in cell morphology. These results indicate that, although correlated, Hsp27 phosphorylation is not required for HL-60 cell differentiation. However, the results do not exclude that increased Hsp27 expression is involved in HL-60 cell differentiation.

Antigens, Surface↗
PubMed1996

Hypo-osmotic cell swelling activates the p38 MAP kinase signalling cascade.

Hypo-osmotic swelling of human Intestine 407 cells leads to a significant increase of intracellular MAPKAP-kinase 2 activity and Hsp27 phosphorylation. Pre-treatment of the cells with the p38 MAP kinase inhibitor SB-203580 blocks this activation, indicating that the hypotonicity-induced activation of MAPKAP kinase 2 is, similarly to that described for hyperosmotic treatment, the result of an activated p38 MAP kinase cascade. The activation of MAPKAP kinase 2 proceeds with kinetics similar to that of one of the first physiological responses of hypo-osmotic treatment, the opening of compensatory Cl- channels. However, inhibition of the p38 MAP kinase cascade does not block the osmo-sensitive anion efflux and, vice versa, activation of p38 MAP kinase by cytokines and anisomycin does not increase the efflux. These results indicate that the p38 MAP kinase cascade is not directly involved in Cl- channel activation but instead may play a role in subsequent cellular repair processes.

Anisomycin↗
PubMed1996

3pK, a novel mitogen-activated protein (MAP) kinase-activated protein kinase, is targeted by three MAP kinase pathways.

Recently we have identified a mitogen-activated protein kinase (MAPK)-activated protein kinase, named 3pK (G. Sithanandam, F. Latif, U. Smola, R. A. Bernal, F.-M. Duh, H. Li, I. Kuzmin, V. Wixler, L. Geil, S. Shresta, P. A. Lloyd, S. Bader, Y. Sekido, K. D. Tartof, V. I. Kashuba, E. R. Zabarovsky, M. Dean, G. Klein, B. Zbar, M. I. Lerman, J. D. Minna, U. R. Rapp, and A. Allikmets, Mol. Cell. Biol. 16:868-876, 1996). In vitro characterization of the kinase revealed that 3pK is activated by ERK. It was further shown that 3pK is phosphorylated in vivo after stimulation of cells with serum. However, the in vivo relevance of this observation in terms of involvement of the Raf/MEK/ERK cascade has not been established. Here we show that 3pK is activated in vivo by the growth inducers serum and tetradecanoyl phorbol acetate in promyelocytic HL60 cells and transiently transfected embryonic kidney 293 cells. Activation of 3pK was Raf dependent and was mediated by the Raf/MEK/ERK kinase cascade. 3pK was also shown to be activated after stress stimulation of cells. In vitro studies with recombinant proteins demonstrate that in addition to ERK, members of other subgroups of the MAPK family, namely, p38RK and Jun-N-terminal kinases/stress-activated protein kinases, were also able to phosphorylate and activate 3pK. Cotransfection experiments as well as the use of a specific inhibitor of p38RK showed that these in vitro upstream activators also function in vivo, identifying 3pK as the first kinase to be activated through all three MAPK cascades. Thus, 3pK is a novel convergence point of different MAPK pathways and could function as an integrative element of signaling in both mitogen and stress responses.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1995

Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif.

A recently described downstream target of mitogen-activated protein kinases (MAPKs) is the MAPK-activated protein (MAPKAP) kinase 2 which has been shown to be responsible for small heat shock protein phosphorylation. We have analyzed the mechanism of MAPKAP kinase 2 activation by MAPK phosphorylation using a recombinant MAPKAP kinase 2-fusion protein, p44MAPK and p38/40MAPK in vitro and using an epitope-tagged MAPKAP kinase 2 in heat-shocked NIH 3T3 cells. It is demonstrated that, in addition to the known phosphorylation of the threonine residue carboxyl-terminal to the catalytic domain, Thr-317, activation of MAPKAP kinase 2 in vitro and in vivo is dependent on phosphorylation of a second threonine residue, Thr-205, which is located within the catalytic domain and which is highly conserved in several protein kinases. Constitutive activation of MAPKAP kinase 2 is obtained by replacement of both of these threonine residues by glutamic acid. A constitutively active form of MAPKAP kinase 2 is also obtained by deletion of a carboxyl-terminal region containing Thr-317 and the A-helix motif or by replacing the conserved residues of the A-helix. These data suggest a dual mechanism of MAPKAP kinase 2 activation by phosphorylation of Thr-205 inside the catalytic domain and by phosphorylation of Thr-317 outside the catalytic domain involving an autoinhibitory A-helix motif.

3T3 Cells↗