| Create a free account, build a dictionary with saved terms to re-use later! |
(4 coded questions)  |
Show articles that do not have abstracts
|
| Humans or Animals | | Humans Animals
| | | Type of Article | | Clinical Trial Editorial Letter Meta-Analysis Practice Guideline Randomized Controlled Trial Review Addresses Bibliography Biography Case Reports Classical Article Clinical Conference Clinical Trial, Phase I Clinical Trial, Phase II Clinical Trial, Phase III Clinical Trial, Phase IV Comment Comparative Study Consensus Development Conference Consensus Development Conference, NIH Controlled Clinical Trial Corrected and Republished Article Dictionary Directory Duplicate Publication English Abstract Evaluation Studies Festschrift Government Publications Guideline Historical Article Interview In Vitro Journal Article Lectures Legal Cases Legislation Multicenter Study News Newspaper Article Overall Patient Education Handout Periodical Index Published Erratum Retracted Publication Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Retraction of Publication Scientific Integrity Review Support of Research Technical Report Twin Study Validation Studies Not a Primary Study or Review Unknown Primary Study Case Series Case Control Cohort Study Observational Study Qualitative Research CBA or ITS Registry Double Blind Controlled before after study Quasi-randomized trial Simple before after study Cluster-RCT Non-Randomized Study Report Book Book chapter Dissertation Conference procedings Secondary Research Not RCT
| | | Ages | | All Infant: birth-23 months All Child: 0-18 years All Adult: 19+ years Newborn: birth-1 month Infant: 1-23 months Preschool Child: 2-5 years Child: 6-12 years Adolescent: 13-18 years Adult: 19-44 years Middle Aged: 45-64 years Middle Aged + Aged: 45+ years Aged: 65+ years 80 and over: 80+ years Undetermined
| | | Language | | English French German Italian Japanese Russian Spanish Afrikaans Albanian Unknown Arabic Armenian Azerbaijani Bosnian Bulgarian Catalan Chinese Croatian Czech Danish Dutch Esperanto Estonian Finnish Georgian Greek, Modern Hebrew Hindi Hungarian Icelandic Indonesian Kinyarwanda Korean Latin Latvian Lithuanian Macedonian Malay Malayalam Maori Multiple Languages Norwegian Persian Polish Portuguese Pushto Romanian Sanskrit Scottish gaelic Serbian Slovak Slovenian Swedish Thai Turkish Ukrainian Vietnamese Not English Not French
| |
|
(1-25 of 5,132) |
Sort By:
|
Took: 0.729 seconds to search 17,750,454 |
R A Dieter,R A Dieter,D L Dieter,R S Dieter,B Dieter On July 27, 1989, six men and 39 sled dogs embarked on the first trans-Antarctic dog, sled, and ski crossing. Data sheets were developed and a review of their day-by-day reports was carried out. The period of time covered is November 3, 1989, to February 10, 1990. Miles traveled were recorded for e... ( view more )ach day and varied from no progress to 31 miles for a single day. A running account of the total miles traveled was also maintained in relationship to the number of days traveled. Radio contact was maintained when conditions permitted. They were able to make calls home and as far away as Paris, France. The time traveled was summarized where recorded and weather conditions particularly were reviewed and maintained. Land conditions, visibility, and cloud formations were discussed. The average temperature varied from -8 degrees C to -48 degrees C (-54 degrees F). Wind conditions and land locations were recorded, as were difficulties encountered on each day. High-calorie foods were eaten. One dog ate as many as 12,000 calories per day. Following a review of appropriate topics, a summary of the conditions is given. ( view less ) Robert S Dieter,Raymond A Dieter,Raymond A Dieter,John P Pacanowski,Micheal J Costanza,William W Chu,Eugene A Gulliver BACKGROUND: Valvular heart disease represents a significant burden to patients with cardiovascular diseases. Surgical treatment of diseased heart valves represents a significant advancement for these patients. However, there are specific complications related to prosthetic valves, including valve t... ( view more )hrombosis. METHODS: Review article. RESULTS: Thrombosis of a prosthetic heart valve can present with gradual cardiac decline, embolic phenomena, or frank cardiogenic shock. The diagnosis of prosthetic valve thrombosis is by history, physical examination, and by an imaging modality. Treatment of the thrombosed valve is either surgical or with thrombolysis. Both modalities have significant morbidity and mortality. CONCLUSION: Treatment of valvular heart disease does not remove the patient from significant risks. Inherent to a prosthetic heart valve is the risk for valvular thrombosis. Prompt recognition and treatment of prosthetic valve thrombosis is important. ( view less ) R A Dieter,D L Dieter,R A Dieter,B Forbes OBJECTIVE: Provide a descriptive review of bear and human interactions in the United States. STUDY DESIGN: Descriptive review. RESULTS: The bear population in the United States includes the grizzly bear, the polar bear, and the black bear, including the glacier phase or blue bear. As the human popu... ( view more )lation grew and remote or wilderness access improved, the bear population suffered both in total numbers and safe habitat. Conservation efforts, such as hunting restrictions and habitat enhancement, have helped to increase the total numbers of bears on the North American continent. The chance of a human encountering a bear increases as the remote bear territory diminishes. Bear incidents are widely publicized, though few serious incidents occur. The authors have direct knowledge of these bear-human encounters in Alaska. Serious human injuries from black bears, or maulings, including fatalities are uncommon. Grizzly bears when trapped or stimulated may be very dangerous. The polar bear sees everything that moves or has color, as potential food, and therefore, will attack seemingly unprovoked. CONCLUSIONS: The chance of a human encountering a bear increases as the remote bear territory diminishes. Bear incidents are widely publicized, though few serious incidents occur. ( view less ) R A Dieter,R S Dieter,R A Dieter,G Gulliver OBJECTIVE: Review zoonotic diseases associated with Canadian geese. STUDY DESIGN: Review article: A review of the multiple physical, microbiologic and safety concerns, and methods used in controlling this potential problem. RESULTS: Over the last decade the Canadian goose population (protected by i... ( view more )nternational treaties and protection acts) has increased rapidly such that in many cities they have become a pest rather than an admired wild bird. Their increasing numbers have caused a number of potential healthcare concerns including: physical, bacterial, parasitic, allergic and viral potential problems. The Canadian goose fecal droppings of one per minute have caused falls and the flying geese have caused air traffic accidents. Bacterial concerns, including botulism, salmonella and E. coli have all been reviewed and presented concerns. The viral Newcastle disease may be detected with hemagglutination studies and the Giardia psittaci parasites have been repeatedly found in their droppings. The Cryptosporidium parvum oocytes have been present on stool study. CONCLUSIONS: Definite links to human infectious diseases have been difficult to prove. Revision of the current laws and new control programs must be developed. ( view less ) Stefan Oswald,Jörg König,Dieter Lütjohann,Thomas Giessmann,Heyo K Kroemer,Christian Rimmbach,Dieter Rosskopf,Martin F Fromm,Werner Siegmund OBJECTIVES: Genetic variability in hepatic uptake was recently shown to influence the disposition and cholesterol-lowering effects of statins. Ezetimibe, an inhibitor of the intestinal cholesterol uptake protein Niemann-Pick C 1 like 1, is another drug for which genetic polymorphisms of hepatic org... ( view more )anic anion transporting polypeptides (OATPs) are expected to be of clinical relevance because ezetimibe undergoes intensive enterohepatic circulation for which hepatic uptake transporters may be rate-limiting determinants. METHODS: Using OATP1B3-, OATP2B1-, and OATP1B1-transfected HEK cells, including the OATP1B1 variants OATP1B1*1b and OATP1B1*5, we measured the uptake of ezetimibe and its glucuronide and we analyzed the competition with the common OATP-substrate bromosulfophthalein. Disposition and sterol-lowering effects of 20-mg ezetimibe were measured in 35 healthy participants genotyped for OATP1B1, ABCB1, ABCC2, and UGT1A1. RESULTS: Ezetimibe glucuronide inhibited bromosulfophthalein uptake in all OATP-transfected cells (50% inhibitory concentration (IC50): 0.14-0.26 mumol/l) whereas ezetimibe was 30-100 times less potent. Only the glucuronide was accumulated significantly in cells expressing OATP1B1 and OATP2B1. Its uptake in cells expressing OATP1B1*1b and *5 was reduced. In-vivo studies showed there was a gene-dose-dependent decrease in the area under the curve of ezetimibe in participants with the OATP1B1*1b protein (*1a/*1a, N=12, 112+/-66 ngxh/ml vs. *1a/*1b, N=8, 88+/-39 ngxh/ml vs. *1b/*1b, N=5, 55+/-18 ngxh/ml; Jonkheere-Terpstra, P=0.041) and a tendency for increased glucuronide exposure (704+/-296 vs. 878+/-369 vs. 1059+/-363 ngxh/ml; P=0.092). Fecal ezetimibe excretion was significantly decreased whereas renal glucuronide excretion was increased in carriers of *1b/*1b. Fecal excretion was also diminished in carriers of OATP1B1*5 and *15. The sterol-lowering effect of ezetimibe was not influenced by OATP1B1 polymorphisms. CONCLUSION: Pharmacokinetics of ezetimibe is influenced by OATP1B1 polymorphisms in healthy participants after single dose administration. ( view less ) Michele Salanova,Gudrun Schiffl,Jörn Rittweger,Dieter Felsenberg,Dieter Blottner The ryanodine receptor type-I (RyR1) is one key player of the excitation-contraction coupling (E-CC) machinery. However, RyR1 expression in human skeletal muscle disuse and plasticity changes are not well documented. We studied the expression and the functional modifications of RyR1 following prolo... ( view more )nged bed rest (BR) without and with exercise countermeasure (Resistive Vibration Exercise, RVE). Soleus biopsies were taken from a non-trained control (BR-CTRL) and trained (BR-RVE) group (each n = 10) before and after BR. In BR-CTRL group, a fibre type-specific immunopattern of RyR1 (type-I < type-II) was documented, and RyR1 immunofluorescence intensity and protein expression together with [(3)H]ryanodine binding were decreased after BR. In BR-RVE group, RyR1 immunosignals were increased and fiber type specificity was no longer present. RyR1 protein expression was unchanged, whereas [(3)H]ryanodine binding increased after BR. Confocal and biochemical analysis confirmed subcellular co-localisation and protein-protein interaction of RyR1 with nitric oxide (NO)-synthase type-1 (NOS1). S-nitrosylation of RyR1 was increased in BR-CTRLpost only, suggesting a reduction of RyR1 open channel probability by nitrosylation mechanisms following prolonged disuse. We conclude that following extended body deconditioning in bed rest, RVE countermeasure maintained normal RyR1 expression and nitrosylation patterns required for adequate E-CC in human performance control. ( view less ) Dorina M Opris,Alexander Ossenbach,Dieter Lentz,A Dieter SchlüterThe synthesis of a set of bipyridine-containing macrocycles by oxidative acetylene-acetylene dimerization is described. The cycles are separated by preparative GPC, and the smallest homologue is analyzed by single-crystal X-ray diffraction, which shows a layered structure with channels that are par... ( view more )tially filled with parts of the flexible chains of adjacent macrocycles. The cyclic trimer has a D 3 h symmetry and is a possible candidate for the formation of metal organic supramolecular assemblies on surfaces. ( view less ) Kira Endres,Rudolf Marx,Joachim Tinschert,Dieter Christian Wirtz,Christian Stoll,Dieter Riediger,Ralf Smeets BACKGROUND: The current surgical therapy of midfacial fractures involves internal fixation in which bone fragments are fixed in their anatomical positions with osteosynthesis plates and corresponding screws until bone healing is complete. This often causes new fractures to fragile bones while drill... ( view more )ing pilot holes or trying to insert screws. The adhesive fixation of osteosynthesis plates using PMMA bone cement could offer a viable alternative for fixing the plates without screws. In order to achieve the adhesive bonding of bone cement to cortical bone in the viscerocranium, an amphiphilic bone bonding agent was created, analogous to the dentin bonding agents currently on the market. METHODS: The adhesive bonding strengths were measured using tension tests. For this, metal plates with 2.0 mm diameter screw holes were cemented with PMMA bone cement to cortical bovine bone samples from the femur diaphysis. The bone was conditioned with an amphiphilic bone bonding agent prior to cementing. The samples were stored for 1 to 42 days at 37 degrees C, either moist or completely submerged in an isotonic NaCl-solution, and then subjected to the tension tests. RESULTS: Without the bone bonding agent, the bonding strength was close to zero (0.2 MPa). Primary stability with bone bonding agent is considered to be at ca. 8 MPa. Moist storage over 42 days resulted in decreased adhesion forces of ca. 6 MPa. Wet storage resulted in relatively constant bonding strengths of ca. 8 MPa. CONCLUSION: A new amphiphilic bone bonding agent was developed, which builds an optimizied interlayer between the hydrophilic bone surface and the hydrophobic PMMA bone cement and thus leads to adhesive bonding between them. Our in vitro investigations demonstrated the adhesive bonding of PMMA bone cement to cortical bone, which was also stable against hydrolysis. The newly developed adhesive fixing technique could be applied clinically when the fixation of osteosynthesis plates with screws is impossible. With the detected adhesion forces of ca. 6 to 8 MPa, it is assumed that the adhesive fixation system is able to secure bone fragments from the non-load bearing midfacial regions in their orthotopic positions until fracture consolidation is complete. ( view less ) Yujie Li,Hans Dieter Schmitt,Dieter Gallwitz,Ren-Wang PengYpt/Rab GTPases and Sec1/Munc18 (SM) proteins are key components of the membrane fusion machinery. Here, we describe new mutants of the yeast SM protein Sly1 that specifically bypass the need for GTPases Ypt1 and Ypt6 in vesicular transport. All sequence alterations are confined to a short alpha-he... ( view more )lix (alpha-20), which is conserved in fungal Sly1 proteins and, when deleted, results in GTPase suppression. Whereas Sly1p of the evolutionarily distant fission yeast Schizosaccharomyces pombe can functionally replace Sly1p in Sacchromyces cerevisiae, mammalian homologues cannot. This indicates that alpha-20 in fungal Sly1p plays an important role in mediating Ypt/Rab-regulated Sly1p function in membrane fusion. ( view less ) Dieter Helm,Dieter Eis Between 1999 and 2003 all consecutive outpatients of the environmental medicine unit of the Charité hospital in Berlin were invited to participate in a study on environmentally related disorders. One hundred and sixty-nine of the patients completed a psychosocial questionnaire which comprised SCL-9... ( view more )0-R and 14 other tests. When compared with clinical controls, SCL-90-R mean scores of the environmental patients (EP) were found to lie in between those of inpatients of a psychosomatic clinic and melanoma aftercare patients; but they were, with exception of the somatisation dimension, much closer to the latter. Application of the TwoStep Cluster component of SPSS resulted in three subgroups with high, moderate and low scores which were significantly different (p<0.001) although separation was incomplete (87% correct identification; cross-validated discriminant analysis). With all subgroups, scores for somatisation, depression and obsessive compulsion were highest and those for phobic anxiety and psychoticism were lowest. SCL-90-R scores correlated well with results of the Freiburg Personality Inventory, Whiteley Index of hypochondriasis, the short form health questionnaire (SF-36), and the Composite International Diagnostic Interview (CIDI). Hierarchical grouping (average linkage between groups), performed with involvement of SCL-90-R data from literature, resulted in a dendrogram with three distinct groups and three outliers. EP with low SCL-90-R scores were assigned to a group which comprised also general populations (USA, Germany), allergy patients, and melanoma controls. Those with moderate SCL-90-R scores were placed in a group together with chronic pain patients, and 26 'environmentally ill' subjects. The third subgroup of EP formed a cluster with our psychosomatic controls, psychosomatic patients from another study, depressed people, and patients undergoing psychotherapy. The three outliers of the dendrogram, however, were SCL-90-R profiles obtained from persons with toxic waste exposure, neurotoxic workplace exposure or with solvent-induced chronic toxic encephalopathy. ( view less ) Markus Stoeckli,Dieter Staab,Alain Schweitzer,James Gardiner,Dieter SeebachMass spectrometric imaging was applied to assess compound distributions on whole-body sections of mice after i.v. dosing of a beta-peptide and an alpha-peptide control. Animals were sacrificed at different time points (5 min, 1 h, 24 h) post-dose, providing simultaneous spatial as well as kinetic i... ( view more )nformation. As a result of this study, no detection of the alpha-peptide control was observed at 1 h post-dose, while retention of the beta-peptide was observed for longer than 24 h post-dose. ( view less ) Marie Kalbacova,Sophie Roessler,Ute Hempel,Roman Tsaryk,Kirsten Peters,Dieter Scharnweber,James C Kirkpatrick,Peter Dieter Nowadays aseptic loosening is the most common cause of orthopaedic implant failure. Some of its reasons have already been described up to now; however, others remain still hypothetical. Besides the inflammatory response to wear particles originating at different sources, the role of reactive oxygen... ( view more ) species as products of cellular reactions and/or as a result of the process of corrosion of an implant leading to implant failure has recently been discussed too. In the present study, we used a galvanostatic polarization to simulate the cathodic partial reaction of the corrosion process at a titanium alloy surface. With respect to cells occurring at the interface of a metal implant, the behaviour of osteoblasts and monocytes/macrophages was investigated. It has been found that cathodic polarization of Ti6Al4V induces an increase in the level of intracellular reactive oxygen species as well as suppressing the metabolic activity of cells in a dose-dependent manner. This is in agreement with the results obtained with cells after external addition of hydrogen peroxide as another kind of oxidative stress. In both approaches, monocytes/macrophages show a higher tolerance to oxidative stress than osteoblasts. It could be concluded that the electrochemical setup developed induced intracellular changes occurring during oxidative stress and it could be used for future detailed analysis of the consequences of corrosion processes for cellular reactions. ( view less ) Heike Möhlig,Sabine Mathieu,Lutz Thon,Marie-Catherine Frederiksen,Diane M Ward,Jerry Kaplan,Stefan Schütze,Dieter Kabelitz,Dieter Adam FAN (factor associated with neutral sphingomyelinase [N-SMase] activation) exhibits striking structural homologies to Lyst (lysosomal trafficking regulator), a BEACH protein whose inactivation causes formation of giant lysosomes/Chediak-Higashi syndrome. Here, we show that cells lacking FAN show a ... ( view more )statistically significant increase in lysosome size (although less pronounced as Lyst), pointing to previously unrecognized functions of FAN in regulation of the lysosomal compartment. Since FAN regulates activation of N-SMase in complex with receptor for activated C-kinase (RACK)1, a scaffolding protein that recruits and stabilizes activated protein kinase C (PKC) isotypes at cellular membranes, and since an abnormal (calpain-mediated) downregulation/membrane recruitment of PKC has been linked to the defects observed in Lyst-deficient cells, we assessed whether PKC is also of relevance in FAN signaling. Our results demonstrate that activation of PKC is not required for regulation of N-SMase by FAN/RACK1. Conversely, activation of PKC and recruitment/stabilization by RACK1 occurs uniformly in the presence or absence of FAN (and equally, Lyst). Furthermore, regulation of lysosome size by FAN is not coupled to an abnormal downregulation/membrane recruitment of PKC by calpain. Identical results were obtained for Lyst, questioning the previously reported relevance of PKC for formation of giant lysosomes and in Chediak-Higashi syndrome. In summary, FAN mediates activation of N-SMase as well as regulation of lysosome size by signaling pathways that operate independent from activation/membrane recruitment of PKC. ( view less ) Lothar Faber,Dirk Welge,Dieter Fassbender,Henning K Schmidt,Dieter Horstkotte,Hubert Seggewiss AIM: To provide tools for predicting the course of AV conduction disturbances after ethanol-induced septal ablation (PTSMA) for hypertrophic obstructive cardiomyopathy (HOCM). METHODS AND RESULTS: Based on a scoring system developed 1996-1998 and including parameters from baseline ECG, heart rate p... ( view more )rofile, severity of outflow obstruction (LVOTO), peri-interventional enzyme kinetics, and peri-interventional conduction problems, the risk of permanent AV block following PTSMA was assessed in 155 consecutive HOCM patients (pts.; mean age: 53+/-13 years) between 1999 and 2004. During PTSMA with 2.1+/-0.5 ml of ethanol, transient complete AV block occurred in 71 pts. (46%). Pts. were grouped into a low, intermediate, and high risk group for permanent conduction damage, and treated accordingly (early discharge from monitoring, prolonged monitoring, early DDD-PM implantation). Permanent pacing was necessary in 11 cases (7%), 0/116 of these (0%) in the low, 4/31 (13%) in the intermediate, and 7/8 (87%) in the high-risk group. While a new right bundle branch block was the most frequent ECG finding after PTSMA, a left bundle branch block at baseline was associated with 4 of the 11 DDD-PM implantations (p<0.0001). In-hospital mortality was 0%, short-term (3-months) follow up was complete. During follow-up, AV conduction recovered in 4 pts. (46%) with a DDD-PM. New onset AV blocks did not occur. Significant improvement of symptoms was reported by 141 pts. (91%). CONCLUSIONS: Catheter-based septal ablation is an effective non-surgical technique for reducing symptoms and outflow gradients in HOCM. The proposed scoring system appears to reliably discriminate pts. with a high risk for permanent PM dependency from those with stable AV conduction after PTSMA. Pts. with left bundle branch block at baseline should undergo DDD-PM implantation prior to ablation. ( view less ) Roland Vogel,Bernhard Tändler,Dieter Voigt,Dieter Jehnichen,Liane Häussler,Lutz Peitzsch,Harald BrünigThis paper reports on an attempt to use reactive extrusion with peroxide as a comfortable pathway for improvement of the crystallization of poly(3-hydroxybutyrate) in a melt spinning process. At first, rheological and thermal properties of the modified melts are determined in order to assess the ef... ( view more )fect of nucleation. Then spinning tests are carried out. Molecular weights and molecular weight distributions of the spun fibers are determined by chromatographic methods. Average crystallite size is measured by wide angle X-ray scattering. Thermal and textile properties of the spun PHB fibers are also determined. An estimation of the improvement of the crystallization in the spinline and of the inhibition of the secondary crystallization in the fibers from the use of the described way of reactive extrusion is given. ( view less ) Roman Tsaryk,Marie Kalbacova,Ute Hempel,Dieter Scharnweber,Ronald E Unger,Peter Dieter,C James Kirkpatrick,Kirsten Peters Titanium and its alloys are amongst the most frequently used materials in bone and dental implantology. The good biocompatibility of titanium(-alloys) is attributed to the formation of a titanium oxide layer on the implant surface. However, implant failures do occur and this appears to be due to ti... ( view more )tanium corrosion. Thus, cells participating in the wound healing processes around an implanted material, among them endothelial cells, might be subjected to reactive oxygen species (ROS) formed by electrochemical processes during titanium corrosion. Therefore, we studied the response of endothelial cells grown on Ti6Al4V alloy to H(2)O(2) and compared this with the response of endothelial cells grown on cell culture polystyrene (PS). We could show that although the cell number was the same on both surfaces, metabolic activity of endothelial cells grown on Ti6Al4V alloy was reduced compared to the cells on PS and further decreased following prototypic oxidative stress (H(2)O(2)-treatment). The analysis of H(2)O(2)-induced oxidative stress showed a higher ROS formation in endothelial cells on Ti6Al4V than on PS. This correlated with the depletion of reduced glutathione (GSH) in endothelial cells grown on Ti6Al4V surfaces and indicated permanent oxidative stress. Thus, endothelial cells in direct contact with Ti6Al4V showed signs of oxidative stress and higher impairment of cell vitality after an additional oxidative stress. However, the exact nature of the agent of oxidative stress generated from Ti6Al4V remains unclear and requires further investigation. ( view less ) Michel Faupel,Débora Bonenfant,Patrick Schindler,Eric Bertrand,Dieter Mueller,Markus Stoeckli,Francis Bitsch,Tatiana Rohner,Dieter Staab,Jan Van OostrumSince the completion of the human genome sequencing, our understanding of gene and protein function and their involvement in physiopathological states has increased dramatically, partly due to technological developments in photonics. Photonics is a very active area where new developments occur on a... ( view more ) weekly basis, while established tools are adapted to fulfill the needs of other disciplines like genomics and proteomics. Biophotonics emerged at the interface of photonics and biology as a very straightforward and efficient approach to observe and manipulate living systems. In this chapter, we review the current applications of photonics and imaging to proteomics from 2D gels analysis to molecular imaging. ( view less ) Lutz Thon,Sabine Mathieu,Dieter Kabelitz,Dieter Adam Death receptors such as the 55 kDa tumor necrosis factor (TNF) receptor (TNF-R55) or Fas can initiate both apoptotic (caspase-dependent) and caspase-independent routes to programmed cell death (PCD). Here, we demonstrate for the first time that the single murine receptor for (TNF)-related apoptosis... ( view more )-inducing ligand (mTRAIL-R2) can induce a caspase-independent form of PCD with necrosis-like features in addition to apoptosis. Analysis of morphological and cellular features of caspase-independent PCD in response to TRAIL and TNF suggests that mTRAIL-R2 and TNF-R55 elicit caspase-independent PCD through similar pathways, although without participation of cathepsins. Cells overexpressing acid ceramidase (AC), an enzyme that metabolizes the sphingolipid ceramide, show enhanced survival from TRAIL-induced caspase-independent PCD but not from apoptosis, implicating a function of ceramide as a key mediator in caspase-independent PCD (but not apoptosis) induced by mTRAIL-R2. In concert with the enhanced resistance of AC-overexpressing cells against caspase-independent PCD induced by TNF, our results suggest that ceramide acts as a common mediator of caspase-independent PCD caused by death receptors such as mTRAIL-R2 and TNF-R55. ( view less ) Stefan Oswald,Thomas Giessmann,Dieter Luetjohann,Danilo Wegner,Dieter Rosskopf,Werner Weitschies,Werner Siegmund BACKGROUND AND AIMS: The disposition and sterol-lowering effect of ezetimibe are associated with long-lasting enterosystemic circulation, which is initiated by secretion of ezetimibe and its glucuronide via intestinal P-glycoprotein (P-gp) (ABCB1) and the multidrug resistance-associated protein 2 (... ( view more )MRP2) (ABCC2) into gut lumen. Hepatic uptake and secretion may contribute to recycling. To obtain deeper insight into the intestinal and hepatic processes, the disposition of ezetimibe was studied in the presence of rifampin (INN, rifampicin), a modulator of P-gp, MRP2, and hepatic organic anion (uptake) transporting polypeptides (OATPs) (SLCOs). METHODS: The disposition of ezetimibe (20 mg orally) alone and after coadministration of rifampin (600 mg orally) was measured in a crossover study of 8 healthy subjects with the SLCO1B1 *1a/*1a genotype. Concentrations of ezetimibe and its glucuronide in serum, urine, and feces, as well as cholesterol, lathosterol, and the plant sterols campesterol and sitosterol in serum, were quantified by use of liquid chromatography and gas chromatography with mass spectrometric detection. RESULTS: After rifampin administration, the maximum serum concentrations of ezetimibe and its glucuronide were significantly elevated (12.0+/-4.20 ng/mL versus 4.67+/-2.72 ng/mL, P=.017, and 282+/-73.8 ng/mL versus 107+/-35.3 ng/mL, P=.012, respectively). The area under the curve of ezetimibe was not affected (102+/-37.6 ng.h/mL versus 140+/-86.3 ng.h/mL, P=not significant), whereas that of the glucuronide was markedly increased (2150+/-687 ng.h/mL versus 1030+/-373 ng.h/mL, P=.012). Renal clearance remained unchanged. Fecal excretion of ezetimibe was markedly decreased (7.6+/-2.2 mg versus 10.4+/-1.8 mg, P=.036), whereas renal excretion of the glucuronide was strongly elevated (4.8+/-1.9 mg versus 2.0+/-1.2 mg, P=.049) after coadministration. The onset of a significant sterol-lowering effect of ezetimibe was significantly shortened by rifampin coadministration. CONCLUSIONS: Coadministration of rifampin increases the maximum serum concentrations of ezetimibe but reduces its enterosystemic recycling, most likely by inhibition of the secretion of ezetimibe and its glucuronide via P-gp and MRP2. ( view less ) Mark Oette,Arne Kroidl,Klaus Göbels,Antje Stabbert,Marion Menge,Abdurrahman Sagir,Dieter Kuschak,Tara O'hanley,Johannes G Bode,Dieter Häussinger OBJECTIVES: The success of highly active antiretroviral therapy (HAART) in HIV infection may be influenced by numerous host factors. There is a lack of data presenting a combined assessment of a variety of these parameters for treatment efficacy in clinical routine practice. METHODS: Different indi... ( view more )ces of therapeutic drug monitoring (TDM) were evaluated prospectively in the context of self-reported adherence, health-related quality of life and social determinants, as measured by a questionnaire. RESULTS: A total of 210 individuals were studied between 2002 and 2004, 77% were males, mean age was 44 years, mean CD4 count was 336 cells/mm3 and 63% had a viral load < 50 copies/mL. In univariate analysis, baseline viral load, unscheduled drug levels, a 4 h pharmacokinetic profile (PK-P) at a scheduled visit and self-reported complete adherence within the previous 2 weeks were significantly associated with virological success of HAART at 12 weeks. At 24 weeks, only baseline viral load, the 4 h PK-P and adherence were significantly associated with HAART efficacy. In multivariate analysis, baseline viral load, adherence, unscheduled drug levels, trough levels at a visit with appointment as well as the 4 h PK-P were significantly associated with virological success at 12 weeks. At 24 weeks, only adherence was significantly linked to outcome. The other parameters were not found to have an impact on treatment efficacy. CONCLUSIONS: TDM and self-reported adherence were independently predictive of short-term HAART success in this prospective study. Unscheduled drug measurements provided similar diagnostic information as a 4 h PK-P. Thus, we propose the use of unscheduled drug level monitoring and self-reported adherence to help identify patients with elevated risk of virological failure. ( view less ) Jacek Bulicz,Daniela C G Bertarelli,Dieter Baumert,Friederike Fülle,Christa E Müller,Dieter Heber Amino-substituted pyrido[2,3-d]pyrimidinediones have previously been found to bind to adenosine A1 and A2A receptors in micromolar concentrations. The present study was aimed at studying the structure-activity relationships of this class of compounds in more detail. Most of the investigated compoun... ( view more )ds were provided with polar substituents, such as ethoxycarbonyl groups and basic amino functions, in order to improve their water-solubility. The compounds were synthesized starting from 6-amino-1,3-dimethyluracil via different reaction sequences involving (cyano)acetylation, Vilsmeier formylation, or reaction with diethyl ethoxymethylenemalonate (EMME). The most potent and selective compound of the present series was 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-5-(2-naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (11c) with a Ki value of 5 nM at rat and 25 nM at human A1 receptors. The compound was more than 60-fold selective versus A3 and more than 300-fold selective versus A2A receptors. It showed an over 300-fold improvement with respect to the lead compound. In GTPgammaS binding studies at membranes of Chinese hamster ovary cells recombinantly expressing the human adenosine A1 receptor, 11c behaved as an antagonist with inverse agonistic activity. A regioisomer of 11c, 6-carbethoxy-1,2,3,4-tetrahydro-1,3-dimethyl-7-(2- naphthylmethyl)aminopyrido[2,3-d]pyrimidine-2,4-dione (7a) in which the 2-naphthylmethylamino substituent at position 5 of 11c was moved to the 7-position, was a relatively potent (Ki=226 nM) and selective (>20-fold) A3 ligand. In the series of compounds lacking an electron-withdrawing ethoxycarbonyl or cyano substituent in the 6-position, compounds with high affinity for adenosine A2A receptors were identified, such as 1,2,3,4-tetrahydro-1,3-dimethyl-5-(1-naphthyl)aminopyrido[2,3-d]pyrimidine-2,4-dione 16b (Ki human A2A=81.3 nM, Ki human A1=153 nM, and Ki human A3>10,000 nM). ( view less ) Fabrice Raynaud,Raynaud Fabrice,Carole Jond-Necand,Jond-Necand Carole,Anne Marcilhac,Marcilhac Anne,Dieter Fürst,Fürst Dieter,Yves Benyamin,Benyamin Yves Calpains are a family of calcium-dependent cysteine-proteases involved in cytoskeleton remodelling and muscle differentiation. In a recent study, we observed the presence of calpain 1 in the muscle contractile apparatus and specifically in the N1- and N2-lines. This calpain isoform was found to be ... ( view more )involved in the degradation of muscle fibres via proteolysis of key proteins in Z-disk and costameric junctions. The goal of this study was to determine whether gamma-filamin--a specific muscle isoform of the filamin family--is a calpain 1 substrate and to characterise this interaction. Gamma-filamin is a major muscle architectural protein located in the Z-line and under the sarcolemmal membrane. This protein is a component of the chain binding the sarcolemma to the sarcomeric structure. In this study, we found that gamma-filamin formed a stable complex in vitro and in cells with calpain 1 in the absence of calcium stimulation. We also located the binding domains in the C-terminus of gamma-filamin with a cleavage site between serine 2626 and serine 2627 in the hinge 2 region. The catalytic (80 kDa) and regulatory (28 kDa) subunits of calpain 1 are both involved in high affinity binding at gamma-filamin. Moreover, we showed that phosphorylation of the filamin C-terminus domain by PKC alpha protected gamma-filamin against proteolysis by calpain 1 in COS cells. Stimulation of PKC activity in myotubes, prevented gamma-filamin proteolysis by calpain and resulted in an increase in myotube adhesion. ( view less ) Christian Peifer,Thomas Stoiber,Eberhard Unger,Frank Totzke,Christoph Schächtele,Dieter Marmé,Ruth Brenk,Gerhard Klebe,Dieter Schollmeyer,Gerd Dannhardt The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely related to this lead, no other compound was found to... ( view more ) be active in the tubulin polymerization assay. However, by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target. Indeed, molecular modeling studies suggest a reasonable binding mode of 10 at the ATP-binding site of the model kinase CDK2. Motivated by these results, analogues of 10 were screened for inhibitory activity in a panel of 12 selected protein kinases and a high affinity of 10 to VEGF-R2 was found showing an IC50 of 2.5 nM. Structure-activity relationships (SAR) for this compound series with the isolated enzyme and equivalent antiangiogenic activity in the chick embryo assay are presented herein. ( view less ) Markus Stoeckli,Richard Knochenmuss,Gregor McCombie,Dieter Mueller,Tatiana Rohner,Dieter Staab,Karl-Heinz WiederholdLabel-free molecular imaging by mass spectrometry allows simultaneous mapping of multiple analytes in biological tissue sections. In this chapter, the application of this new technology to the detection Abeta peptides in mouse brain sections is discussed. Wolf D Lehmann,Junhua Wei,Chien-Wen Hung,Hans-Joachim Gabius,Dieter Kirsch,Bernhard Spengler,Dieter Kübler In an analysis of a combined chymotrypsin/AspN digest of galectin-3 by positive ion nano-electrospray ionisation mass spectrometry (nanoESI-MS) several peptides were observed which showed metal adduct ions as their most abundant ion signals. The most prominent adduct ions were observed at m/z value... ( view more )s corresponding to [M+40]2+, [M+41]3+, and [M+42]4+ ions. Detailed investigation of the [M+40]2+ ion of the peptide GAPAGPLIVPY showed that it was not, as originally expected, a [M+H+39K]2+ adduct ion but had the composition [M+40Ca]2+. This was verified by several approaches: (i) nanoESI-MS/MS of the [M+Ca]2+ adduct ions resulted in the virtually exclusive formation of doubly charged fragment ions; (ii) mass determination by quadrupole time-of-flight (QTOF)-MS provided a preliminary identification; and (iii) accurate mass measurement using nanoESI Fourier transform ion cyclotron resonance (FTICR)-MS at a mass resolving power of 500 000 allowed the specific detection and identification of the isobaric ion pairs [M+40Ca]2+/[M+H+39K]2+ and [M+24Mg]2+/[M+H+23Na]2+. All peptides in the chymotryptic galectin-3 digest without a basic residue (K or R) showed addition of calcium as the most prominent ionisation principle. A further common feature of these nonbasic peptides was the presence of several proline residues, which is assumed to be a factor promoting the intense addition of calcium. It was observed that the common trace levels of sodium and calcium in analytical grade solvents (about 1-10 microM) are sufficient to generate the [M+H+23Na]2+ and [M+40Ca]2+ ions as the most prominent species of the peptide GAPAGPLIVPY. We conclude that the sequence motifs P-XX-P and P-XXX-P favour the solvation of alkaline earth ions in ESI-MS. In view of the successful detection of physiological Ca/protein interactions by ESI-MS, this finding may point to a solvation of Ca2+ by galectin in solution. The findings open new routes of research in the study of metal/protein and metal/peptide interactions ( view less )
|
|
|