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Biomedical subjects

B Jung

Publications and source records attributed to B Jung.

At least 19 recordsLinked to original sources

Quantitative 1H-magnetic resonance spectroscopy of human brain: Influence of composition and parameterization of the basis set in linear combination model-fitting.

Localized short-echo-time (1)H-MR spectra of human brain contain contributions of many low-molecular-weight metabolites and baseline contributions of macromolecules. Two approaches to model such spectra are compared and the data acquisition sequence, optimized for reproducibility, is presented. Modeling relies on prior knowledge constraints and linear combination of metabolite spectra. Investigated was what can be gained by basis parameterization, i.e., description of basis spectra as sums of parametric lineshapes. Effects of basis composition and addition of experimentally measured macromolecular baselines were investigated also. Both fitting methods yielded quantitatively similar values, model deviations, error estimates, and reproducibility in the evaluation of 64 spectra of human gray and white matter from 40 subjects. Major advantages of parameterized basis functions are the possibilities to evaluate fitting parameters separately, to treat subgroup spectra as independent moieties, and to incorporate deviations from straightforward metabolite models. It was found that most of the 22 basis metabolites used may provide meaningful data when comparing patient cohorts. In individual spectra, sums of closely related metabolites are often more meaningful. Inclusion of a macromolecular basis component leads to relatively small, but significantly different tissue content for most metabolites. It provides a means to quantitate baseline contributions that may contain crucial clinical information.

Adolescent↗

Kindling induces the mRNA expression of methyl DNA-binding factors in the adult rat hippocampus.

We have investigated the gene expression responses of a family of methyl CpG-binding domain-containing factors (MeCP2, MBD1, MBD2, and MBD3) in the hippocampus of electrically kindled rats. Expression was examined in both amygdala- and partial perforant-pathway-kindled subjects, 24 h and 28 days following the final stimulation. In general, the responses of MBDs 2 and 3 paralleled each another, both temporally and spatially. The expression of both genes was significantly elevated in all hippocampal subfields at 24 h following either the fifth stage 5 seizure (amygdala kindling) or the 15th stimulation of the perforant pathway. This induced expression was transient, however, as the expression of both genes returned to control levels by 28 days. This pattern of response contrasted to that observed for MeCP2 and MBD1. MeCP2 displayed no change in expression either 24 h or 28 days after amygdala kindling, but did display a late-developing, significant increase in expression in the dentate gyrus at 28 days following perforant-pathway kindling. The expression of MBD1 was unchanged by partial perforant-pathway kindling, but was induced in the dentate gyrus 28 days after amygdala kindling. These results demonstrate that electrical kindling alters the hippocampal expression of methyl DNA-binding factors, but does not affect each factor equivalently. The responsive patterns observed suggest that this family of transcriptional regulators can be differentially altered in the hippocampus by seizure activity.

Amygdala↗

Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil.

Capecitabine is a member of a new class of oral fluoropyrimidines. It is a 5-fluorouracil (5-FU) prodrug, activated by a series of enzymes. Activation has been demonstrated to occur preferentially in tumor tissue, which may explain the favorable balance of efficacy and toxicity of this drug. Cardiotoxicity, a rare but potentially serious adverse effect of 5-FU, has not been reported for capecitabine to date. Here we report a patient who experienced a severe and prolonged acute coronary syndrome during treatment with capecitabine. He had previously developed similar symptoms during treatment with infusional 5-FU. Capecitabine should thus be considered an agent with cardiotoxic potential. This adverse effect should be specifically monitored in all patients treated with capecitabine. Patients with symptoms suggestive of cardiotoxicity during previous treatment with a fluoropyrimidine should not be treated with capecitabine.

Administration, Oral↗

Extensions to the HISA standard--the SynEx computing environment.

OBJECTIVES: This paper reports on the integration work required to support the delivery of healthcare. Specifically, four elements are included being: the DHE (a standards based distributed healthcare environment), Synapses which is a patient record server, XML as a technology to deliver records, and finally two client applications that facilitate structured data entry (SDE) and the remote booking of specialist services. METHODS: A general motivation for the work is presented and augmented on hand of a clinical scenario. Additionally, the adoption of a middleware approach is reviewed. The role of computerised patient records is described followed by an account of a federated record server. The approach favoured by standards bodies in utilising XML is covered and the tailoring to suit the needs of the integration is explained. The main practical challenges in achieving integration are presented, one of these being the mapping between the DHE data model and the Synapses server record architecture. RESULTS: The described environment has been demonstrated to provide the functionality that is required and in addition it has been shown that the engineering challenges can be met in a controlled and orderly manner. CONCLUSIONS: The role of the DHE middleware component acting as an 'anchor' has been shown to be a valid one onto which other specialised components can be added to provide a richer service environment. Additionally, it has been demonstrated that XML is a good candidate technology that facilitates connectivity to client applications over an extranet. The demands inherent in both the clinical scenario and the computerised patient record can be met by the computing environment described in the paper.

Computer Systems↗

Crystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor.

Human macrophage elastase (MMP-12) is a member of the family of matrix metalloproteinases (MMPs) that plays, like other members of the family, an important role in inflammatory processes contributing to tissue remodelling and destruction. In particular, a prominent role of MMP-12 in the destruction of elastin in the lung alveolar wall and the pathogenesis of emphysema has been suggested. It is therefore an attractive therapeutic target. We describe here the crystal structure of the catalytic domain of MMP-12 in complex with a hydroxamic acid inhibitor, CGS27023A. MMP-12 adopts the typical MMP fold and binds a structural zinc ion and three calcium ions in addition to the catalytic zinc ion. The enzyme structure shows an ordered N terminus close to the active site that is identical in conformation with the superactivated form of MMP-8. The S1'-specificity pocket is large and extends into a channel through the protein, which puts MMP-12 into the class of MMPs 3, 8 and 13 with large and open specificity pockets. The two crystallographically independent molecules adopt different conformations of the S1'-loop and its neighbouring loop due to differing crystal packing environments, suggesting that flexibility or the possibility of structural adjustments of these loop segments are intrinsic features of the MMP-12 structure and probably a common feature for all MMPs. The inhibitor binds in a bidentate fashion to the catalytic zinc ion. Its polar groups form hydrogen bonds in a substrate-like manner with beta-strand sIV of the enzyme, while the hydrophobic substituents are either positioned on the protein surface and are solvent-exposed or fill the upper part of the specificity pocket. The present structure enables us to aid the design of potent and selective inhibitors for MMP-12.

Amino Acid Sequence↗

Quantitative (1)H magnetic resonance spectroscopy of myoglobin de- and reoxygenation in skeletal muscle: reproducibility and effects of location and disease.

1H-magnetic resonance spectroscopy ((1)H-MRS) of deoxymyoglobin (DMb) provides a means to noninvasively monitor the oxygenation state of human skeletal muscle in work and disease. As shown in this work, it also offers the opportunity to measure the absolute tissue content of DMb, the basic oxygen consumption of resting muscle, and the reperfusion characteristics after release of a pressure cuff. The methodology to determine these tissue properties simultaneously at two positions along the calf is presented. The obtained values are in agreement with invasive determinations. The reproducibility of the (1)H-MRS measurements is established for healthy controls and patients with peripheral arterial disease (PAD). A location dependence in axial direction, as well as differences between controls and patients are demonstrated for all parameters. The reoxygenation time in particular is expected to provide a means to quantitatively monitor therapies aimed at improving muscular perfusion in these patients.

Adult↗

Quantitation of localized (31)P magnetic resonance spectra based on the reciprocity principle.

There is a need for absolute quantitation methods in (31)P magnetic resonance spectroscopy, because none of the phosphorous-containing metabolites is necessarily constant in pathology. Here, a method for absolute quantitation of in vivo (31)P MR spectra that provides reproducible metabolite contents in institutional or standard units is described. It relies on the reciprocity principle, i.e., the proportionality between the B(1) field map and the map of reception strength for a coil with identical relative current distributions in receive and transmit mode. Cerebral tissue contents of (31)P metabolites were determined in a predominantly white matter-containing location in healthy subjects. The results are in good agreement with the literature and the interexamination coefficient of variance is better than that in most previous studies. A gender difference found for some of the (31)P metabolites may be explained by different voxel composition.

Adenosine Triphosphate↗

Effect of oral D-tagatose on liver volume and hepatic glycogen accumulation in healthy male volunteers.

Standard toxicity tests with high levels of D-tagatose showed a reversible enlargement of the liver in Sprague-Dawley rats without increase of liver enzymes. The present study tests the hypotheses that partial substitution of dietary sucrose by D-tagatose for 28 days increases the volume of human liver and the concentration of liver glycogen. Twelve healthy, male volunteers were studied in a double-blind crossover study with ingestion of D-tagatose (3x15 g daily) and placebo (sucrose, 3x15 g daily) for periods of 28 days each. Liver volume and glycogen concentration have been determined by magnetic resonance (MR) imaging and spectroscopy, which were accompanied by routine medical examinations. MR examinations before and after the treatments revealed no effects (P>0.05) of treatment, period, or subject for changes in liver volume or glycogen concentration. A steady increase of liver volumes, independent of the D-tagatose or placebo intake, has been observed over the study in parallel with a slight increase in body weight. The treatment with D-tagatose was not associated with clinically relevant changes of the examined clinico-chemical and hematological parameters, including liver enzymes and uric acid.

Administration, Oral↗

Bilaminar pattern of tibial condyle cartilage layer on the fat-suppressed 3D gradient echo images: artifact or structural and biochemical difference in composition of cartilage?

The purpose of this study was to examine if an unusual bilaminar pattern of lateral tibial condyle cartilage layer on the fat-suppressed three-dimensional (3D) spoiled gradient echo sequence is artifactual or correlates with structural and/or biochemical composition of cartilage. The laminar appearance of the lateral tibial condyle cartilage layer was studied on fat-suppressed 3D spoiled gradient echo MR images of the knee joint in 67 patients (mean age: 28y) performed at 1.0 Tesla. After i.v. administration of gadopentetate dimeglumine, diffusion of the contrast media into cartilage layer was qualitatively analysed over time on inversion recovery spin echo images of knee joints of five asymptomatic volunteers (mean age: 25y). In a patient with osteosarcoma and total knee replacement, MR examination of cartilage layer of lateral tibial plateau was compared with histologic specimens stained with Safranin-O, demonstrating proteoglycan distribution in cartilage. The retrospective analysis of 67 knee joints revealed a bilaminar appearance of lateral tibial condyle cartilage layer in the gradient echo images in the majority of cases (81%) with a statistically significant tendency to a trilaminar pattern in patients older than 20 years. With i.v. contrast administration, the contrast enhancement was only observed in the superficial zone of tibial cartilage layer. Histologic specimens in one patient demonstrated a good correlation between thickness of proteoglycan-free and proteoglycan-rich laminae of lateral tibial condyle on Safranin-O staining with hyperintense and hypointense zones, respectively, on corresponding fat-suppressed 3D spoiled gradient echo images (correlation coefficient of 0.87). Bilaminar pattern of tibial condyle cartilage layer on fat-suppressed 3D spoiled gradient echo images in younger subjects is not an artifact or an intrachondral lesion, but it may represent a regional difference in composition of extracellular cartilage matrix possibly produced by a highly-oriented collagen fiber structure associated with a high concentration of proteoglycans in the middle and deep portion of the cartilage layer.

Adolescent↗

What do American nephologists think about dialysis modality selection? .

In the United States, 87.3% of the patients with end-stage renal disease (ESRD) requiring dialysis are treated with hemodialysis (HD) and 12.7% with peritoneal dialysis (PD). This represents a greater use of HD than in many other nations. We mailed a survey questionnaire to members of the National Kidney Foundation Council on Dialysis to better understand the attitudes of American nephrologists toward dialysis modality decisions. We received responses from 240 of 507 nephrologists (47.3%). The respondents were heavily involved in clinical dialysis work. Results showed that decisions regarding modality selection were strongly based on patient preference (4.54 on a scale of 1 to 5), quality of life (4.18), morbidity (4.02), and mortality (3.90), whereas the least important factors reported were facility reimbursement (2.09) and physician reimbursement (1.98). When asked about the current use of modalities, hospital-based HD and full-care HD were believed to be overused (2.63 for each on a scale of 1 [vastly overused] to 5 [vastly underused]), whereas home HD (4.29), continuous ambulatory PD (3.71), and cycler PD (3.59) were underused. A hypothetical question about optimal modality distribution to maximize survival or cost-effectiveness showed that HD should constitute 71% or 66% of dialysis (with 11% or 14% in the form of home HD, respectively). PD use would increase between two- and threefold over current practices. Our results suggest that American nephrologists believe home therapies are underused. Because modality distribution is an important determinant of costs and possibly outcomes in patients with ESRD, there is an urgent need for further research in this area.

Cost-Benefit Analysis↗

Progression and NSAID-induced apoptosis in malignant melanomas are independent of cyclooxygenase II.

Cyclooxygenase-II (Cox-II) overexpression is involved in the progression of various subtypes of cancer. We investigated the significance of Cox-II in the progression of malignant melanomas (MMs). Using immunohistology we determined that Cox-II is not expressed in 70 benign and malignant melanocytic tumours. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) were also analysed as controls: the BCCs were consistently Cox-II negative (n = 11), whereas the SCCs showed moderate to strong Cox-II expression in 53% (n = 17). Reverse transcription-polymerase chain reaction and Western blotting of MM cell lines and MM tissues confirmed the lack of Cox-II expression in MM. However, in vitro the Cox-inhibiting non-steroidal anti-inflammatory drug (NSAID) sulindac sulphide (SIS) was significantly more effective in inducing apoptosis than sulindac sulphone (SOS), a derivative with a negligible effect on Cox (P < 0.01). The SIS doses needed for the induction of apoptosis were not significantly different in MM cell lines versus a Cox-II-positive colon carcinoma cell line (HT29). Furthermore, add-back experiments with high doses of the prostaglandins PGE2 and PGF2beta, major Cox-II products, did not abrogate this effect. We conclude that Cox-II expression is not involved in the progression of MM, and NSAID-induced apoptosis in MM cell lines seems to follow pathways independent of Cox-II. Nevertheless, Cox-II inhibitors are still candidates for therapy, though they act via an unknown mechanism.

Adolescent↗

Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke.

Mucus hypersecretion from hyperplastic airway goblet cells is a hallmark of chronic obstructive pulmonary disease (COPD). Although cigarette smoking is thought to be involved in mucus hypersecretion in COPD, the mechanism by which cigarette smoke induces mucus overproduction is unknown. Here we show that activation of epidermal growth factor receptors (EGFR) is responsible for mucin production after inhalation of cigarette smoke in airways in vitro and in vivo. In the airway epithelial cell line NCI-H292, exposure to cigarette smoke upregulated the EGFR mRNA expression and induced activation of EGFR-specific tyrosine phosphorylation, resulting in upregulation of MUC5AC mRNA and protein production, effects that were inhibited completely by selective EGFR tyrosine kinase inhibitors (BIBX1522, AG-1478) and that were decreased by antioxidants. In vivo, cigarette smoke inhalation increased MUC5AC mRNA and goblet cell production in rat airways, effects that were prevented by pretreatment with BIBX1522. These effects may explain the goblet cell hyperplasia that occurs in COPD and may provide a novel strategy for therapy in airway hypersecretory diseases.

Animals↗

[Synthesis and pharmacologic action of chiral fomocaine ((4-[2-methyl-3-(morpholin-4-yl)propyl)benzyl)-phenyl-ether and (4-(1-methyl-3-(morpholin-4-yl)propyl]benzyl)-phenyl-ether). 13. Synthesis of new compounds with local anesthetic action].

The syntheses of two chiral fomocaines namely rac ((4-[2-methyl-3-(morpholin-4-yl)propyl]-benzyl)-phenyl-ether (O/G 3) and rac (4-[1-methyl-3-(morpholin-4-yl)propyl]benzyl)-phenyl-ether) (O/G 5) are reported. These compounds are part of a new research program concerning the relation between chirality and local anaesthetic activity in the group of fomocaines. The yield over five steps is in the range of 9% (O/G 3) up to 19.2% (O/G 5). The racemates were resoluted via the diastereomeric salts formed with (+)- or (-)-camphersulfonic acid. The chromatographic resolution in analytical scale is successful using a Daicel OD-column. The enantiomers are stable. The surface anaesthesia of the racemates as well as of the enantiomeres is weaker in comparison with fomocaine. The rate of tissue irritation is higher. The LD50 (mouse i.v.) is in the range between 290-390 mg/kg, while fomocaine shows a LD50 value of 175 mg/kg.

Anesthetics, Local↗

Dioxygen-binding kinetics and thermodynamics of a series of dicopper(I) complexes with bis[2-(2-pyridyl)ethyl]amine tridendate chelators forming side-on peroxo-bridged dicopper(II) adducts.

Copper-dioxygen interactions are of interest due to their importance in biological systems as reversible O2- carriers, oxygenases, or oxidases and also because of their role in industrial and laboratory oxidation processes. Here we report on the kinetics (stopped-flow, -90 to 10 degrees C) of O2-binding to a series of dicopper(I) complexes, [Cu2(Nn)(MeCN)2]2+ (1Nn) (-(CH2)n- (n = 3-5) linked bis[(2-(2-pyridyl)ethyl]amine, PY2) and their close mononuclear analogue, [(MePY2)Cu(MeCN)]+ (3), which form mu-eta 2:eta 2-peroxodicopper(II) complexes [Cu2(Nn)-(O2)]2+ (2Nn) and [(MePY2)Cu]2(O2)]2+ (4), respectively. The overall kinetic mechanism involves initial reversible (k+,open/k-,open) formation of a nondetectable intermediate O2-adduct [Cu2(Nn)(O2)]2+ (open), suggested to be a CuI...CuII-O2- species, followed by its reversible closure (k+,closed/k-,closed) to form 2Nn. At higher temperatures (253 to 283 K), the first equilibrium lies far to the left and the observed rate law involves a simple reversible binding equilibrium process (kon,high = (k+,open/k-,open)(k+,closed)). From 213 to 233 K, the slow step in the oxygenation is the first reaction (kon,low = k+,open), and first-order behavior (in 1Nn and O2) is observed. For either temperature regime, the delta H++ for formation of 2Nn are low (delta H++ = -11 to 10 kJ/mol; kon,low = 1.1 x 10(3) to 4.1 x 10(3) M-1 s-1, kon,high = 2.2 x 10(3) to 2.8 x 10(4) M-1 s-1), reflecting the likely occurrence of preequilibria. The delta H degree ranges between -81 and -84 kJ mol-1 for the formation of 2Nn, and the corresponding equilibrium constant (K1) increases (3 x 10(8) to 5 x 10(10) M-1; 183 K) going from n = 3 to 5. Below 213 K, the half-life for formation of 2Nn increases with, rather than being independent of, the concentration of 1Nn, probably due to the oligomerization of 1Nn at these temperatures. The O2 reaction chemistry of 3 in CH2Cl2 is complicated, including the presence of induction periods, and could not be fully analyzed. However, qualitative comparisons show the expected slower intermolecular reaction of 3 with O2 compared to the intramolecular first-order reactions of 1Nn. Due to the likelihood of the partial dimerization of 3 in solution, the t1/2 for the formation of 4 remains constant with increasing complex concentration rather than decreasing. Acetonitrile significantly influences the kinetics of the O2 reactions with 1Nn and 3. For 1N4, the presence of MeCN inhibits the formation of a previously (Jung et al, J. Am. Chem. Soc. 1996, 118, 3763-3764) observed intermediate. Small amounts of added MeCN considerably slow the oxygenation rates of 3, inhibit its full formation to 4, and increase the length of the induction period. The results for 1Nn and their mononuclear analogue 3 are presented, and they are compared with each other as well as with other dinucleating dicopper(I) systems.

Copper↗

Effects of high salt diets and taurine on the development of hypertension in the stroke-prone spontaneously hypertensive rat.

Taurine is present in high concentrations in mammalian tissues and has been implicated in cardiovascular control mechanisms. The aim of the present study was to evaluate the ability of taurine to attenuate salt-induced elevations in blood pressure and markers of damage to the kidney and cardiovascular system in stroke prone spontaneously hypertensive rats (SPSHR). Male SPSHR (6 weeks old) were placed on high salt diets that contained 1% (w/w) NaCl added to their normal chow for 84 days and then were switched to 3% added NaCl for the remaining 63 days of the study. SPSHR was given 1.5% taurine in the drinking water (n = 8), a taurine free diet (n = 8) or normal chow (n = 8). A final control group (n = 6) was not given high salt diets. High salt diets caused an acceleration in the development of hypertension in all groups. Taurine supplementation reduced ventricular hypertrophy and decreased urinary excretion of protein and creatinine. The taurine free diet did not alter serum or urinary excretion of taurine, but did result in elevated urinary nitrogen excretion, increased serum cholesterol levels, and impaired performance in a spatial learning task. Alterations in dietary taurine intake did not alter urinary or serum electrolytes (Na+, K+), but taurine supplementation did attenuate a rise in serum calcium seen with the high salt diets. Urinary excretion (microg/24h) of epinephrine and dopamine was significantly reduced in SPSHR given 1% NaCl in the diet, but this effect was not seen in SPSHR on taurine free or supplemented diets. Taurine supplementation showed cardioprotective and renoprotective effects in SPSHR given high salt diets.

Animals↗

Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions.

Survivin is a mitotic spindle-associated protein involved in linking mitotic spindle function to activation of apoptosis in mammalian cells. The structure of the full-length human survivin has been determined by X-ray crystallography to 2.7 A. Strikingly, the structure forms a very unusual bow tie-shaped dimer. It does not dimerize through a C-terminal coiled-coil, contrary to sequence analysis prediction. The C-terminal helices contain hydrophobic clusters with the potential for protein-protein interactions. The unusual shape and dimensions of survivin suggest it serves an adaptor function through its alpha-helical extensions.

Amino Acid Sequence↗

Practical aspects to realize data transfer between a patient administration mastersystem and clinical subsystems using ProtoGen/HL7.

At the Medizinische Einrichtungen Bonn the module IS-H of SAP R/3 is used for patient administration. All clinical subsystems will be provided with patient data using HL7 2.3 messages. These messages are generated from HCM messages a proprietary format of IS-H by means of a communication server. Interface application for subsystems which are not capable of processing HL7 messages are written using the open source C++ class library ProtoGen/HL7. First experiences and remaining problems are discussed.

Data Collection↗

Effect of p21waf1/cip1 transgene on radiation induced apoptosis in T cells.

The cyclin kinase inhibitor p21WAF1/Cip1 is upregulated by the tumor suppressor p53. While p21 is central for the G-1 arrest mediated by p53, it is still unclear if p21 also functions as a downstream effector of p53 dependent apoptosis. Apoptosis induced by DNA damage but not dexamethasone is p53 dependent in thymocytes. To investigate the physiological role of p21 in apoptosis, we have generated transgenic mice in which the p21 transgene is targeted for restricted expression in the T cell lineage. Thymocytes from p21 transgenic mice were hypersensitive to cell death induced by DNA damaging agents such as ionizing radiation and UV, but not be dexamethasone. Irradiated p21 transgenic thymocytes had approximately twofold more apoptotic cells as compared to irradiated age matched littermate control mice. Radiation induced death is comparable in thymocytes from p21 + Bcl2 + double transgenic mice and age matched littermate controls, indicating that the Bcl2 transgene rescues the radiation hypersensitivity imposed by p21. However, thymocytes from p53-/- mice even when they expressed the p21 transgene, were resistant to death induced by radiation. Together these results show that thymocytes from p21 transgenic mice are hypersensitive to radiation induced programmed cell death and suggest that the radiation hypersensitivity of p21 transgenic thymocytes involves p53 dependent pathway and signals in addition to p21.

Animals↗