Drunken driving and renal failure--do you see a link?
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Alcohol Drinking↗
Biomedical subjects
J Wagner
Publications and source records attributed to J Wagner.
Treatment of cardiovascular changes in renal failure--ACE inhibition, endothelin receptor blockade or a combination of both strategies?
ACE-I and specific ETA receptor blockade comparably prevented the development of structural cardiovascular alterations such as LVH, myocardial interstitial expansion and wall thickening of intramyocardial and extracardiac arteries in experimental renal failure. However, the decrease in myocardial capillary supply and the concomitant increase in intercapillary distance could only be prevented by ETA receptor antagonism. These capillary changes which have been shown to occur in experimental renal failure as well as in uraemic patients play an important role in the pathogenesis of reduced cardiac ischaemia tolerance in renal failure. The data argue for a potential role of the local renin-angiotensin system as well as of the ET system in the pathogenesis of cardiovascular changes in renal failure and for ET receptor blockade as a new therapeutic option in the treatment of these alterations. In particular, myocardial capillary supply, which is particularly important for ischaemia tolerance in renal failure, seems to be modulated and regulated predominantly by ET-1. In contrast to what was found with respect to structural and functional changes of the kidney in various experimental models of renal damage, a combination therapy--at least in the doses used--does not seem to provide additional benefit in the prevention of cardiovascular changes compared with the respective monotherapies.
Angiotensin-Converting Enzyme Inhibitors↗
Highlights of the 1998 Institute on Psychiatric Services. Issues in public-sector managed care.
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Humans↗
Angiotensin II receptor type 1 gene expression in human glomerulonephritis and diabetes mellitus.
The renin-angiotensin system plays an important role in the progression of chronic renal disease. Although the expression of renin and angiotensin-converting enzyme in experimental and human renal disease has been well characterized, no information is available regarding human angiotensin type 1 (AT1) receptor expression. The net effect of renin depends on AT1 receptor expression, among other factors. Receptor expression was determined in renal biopsy samples (including all tissue components) and isolated glomeruli from patients with glomerulonephritis (GN) or diabetic nephropathy (non-insulin-dependent diabetes mellitus). Biopsy samples and isolated glomeruli from tumor-free tissue from tumor nephrectomies served as controls. Human AT1 receptor gene expression was determined by quantitative reverse transcription-PCR, using an AT1 receptor deletion mutant as the internal standard. In whole biopsy samples from 37 patients with various types of GN, AT1 receptor mRNA levels were lower, compared with nine control biopsy samples (P < 0.001). AT1 receptor mRNA levels were also significantly lower (P < 0.001) in eight samples from patients with diabetic nephropathy. In microdissected glomeruli, AT1 receptor gene expression was significantly lower in samples from patients (n = 22) with various types of GN, compared with 12 microdissected tumor nephrectomy control samples (P < 0.0023). It is concluded that AT1 receptor mRNA expression is low in glomeruli of patients with chronic renal disease. This may reflect a regulatory response to (inappropriately) high intrarenal angiotensin II concentrations.
Adult↗
Diogenes syndrome and hoarding in the elderly: case reports.
Presented here are two case reports of elderly persons with Diogenes syndrome (variously known as senile breakdown, social breakdown and senile squalor syndrome). Diogenes syndrome is often (but not always) characterized by a tendency to hoard excessively (syllogomania). The first patient was diagnosed as having both a schizotypal personality disorder and obessive-compulsive disorders (OCD) while the second was diagnosed as having a schizoid personality disorder. Only the former demonstrated the tendency to hoard rubbish. The Diogenes syndrome in both cases can be hypothesized to be a reaction to stress in elderly people with certain personality characteristics or as the end stage of a personality disorder. The hoarding behavior that was manifested only in the first case can probably be the result of the presence of an OCD. The authors raise the possibility that OCD may be the cause of hoarding rubbish in those cases of Diogenes syndrome in which hoarding exists and cannot be explained by psychotic disorders, dementia or any other mental disorders due to a general medical condition (GMC) or substance-related disorders.
Aged↗
Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration.
The objective of this study was to accurately determine the within- and between-patient variability in etoposide pharmacokinetics for i.v. and p.o. administered drug. Inter-and intrapatient variability in systemic etoposide exposure was measured following i.v. and p.o. drug administration using stable isotope dilution methodology. Seven patients received 50 mg of etoposide by both p.o. and i.v. routes of administration on three separate occasions 1 month apart. Etoposide plasma concentrations following p.o. and i.v. drug administration were quantitated by liquid chromatography-mass spectrometry for each route of administration. The area under the plasma etoposide concentration versus time curve, plasma etoposide clearance, and etoposide plasma half-life were calculated for each dose of drug. Kinetic measurements following i.v. and p.o. drug administration were compared. The within-patient variation in the areas under the plasma etoposide concentration versus time curves following i.v. drug administration was minimal [coefficient of variation (CV) = 9.3%]. Within-patient variability was increased 2.4-fold with oral drug administration (intrapatient CV = 22.2%). Between-patient variability was roughly three times as great as within-patient variability (interpatient i.v. CV = 28.4%; interpatient p.o. CV = 58.3%). Mean etoposide bioavailability at a dose of 50 mg was 64.6%, again with greater interpatient than intrapatient variability (34.8 versus 22.6%). Greater variation in drug toxicity is expected with p.o. compared with i.v. etoposide use. Administration of repeated doses of etoposide to the same patient should produce less variation in toxicity than between-patient dosing.
Administration, Oral↗
MEDTAG: tag-like semantics for medical document indexing.
Medical documentation is central in health care, as it constitutes the main means of communication between care providers. However, there is a gap to bridge between storing information and extracting the relevant underlying knowledge. We believe natural language processing (NLP) is the best solution to handle such a large amount of textual information. In this paper we describe the construction of a semantic tagset for medical document indexing purposes. Rather than attempting to produce a home-made tagset, we decided to use, as far as possible, standard medicine resources. This step has led us to choose UMLS hierarchical classes as a basis for our tagset. We also show that semantic tagging is not only providing bases for disambiguisation between senses, but is also useful in the query expansion process of the retrieval system. We finally focus on assessing the results of the semantic tagger.
Abstracting and Indexing↗
Combination of gene targeting and substrate trapping to identify substrates of protein tyrosine phosphatases using PTP-PEST as a model.
Identification of physiological substrates of protein tyrosine phosphatases is a key step in understanding the function of these enzymes. We have generated fibroblast cell lines having a gene-targeted PTP-PEST in order to identify potential substrates with the premise that specific substrates of this enzyme would exist in a hyperphosphorylated state. Analysis of the profile of the phosphotyrosine proteins in the PTP-PEST -/- cells revealed the presence of hyperphosphorylated proteins of 180, 130, and 97 kDa when compared to control cells. The p130 was identified as p130(Cas), and direct immunoprecipitates of p130(Cas) demonstrate that this protein is constitutively hyperphosphorylated in cells lacking PTP-PEST. In addition, p130(Cas) was also isolated by the substrate-trapping mutant of PTP-PEST in the PTP-PEST -/- cell lysates. Interestingly, we have demonstrated for the first time that PTP-PEST, through its first proline-rich sequence 332PPKPPR337, interacts with other members of the p130(Cas) family (Hef1 and Sin) via their SH3 domain in vitro. This result suggests that Hef1 and Sin could also be potential substrates of PTP-PEST. In conclusion, we have combined genetic and biochemical strategies to allow the identification of PTP-PEST substrates. This experimental approach could potentially be used to identify substrates of other PTPases. Furthermore, the Cas-like molecules Hef1 and Sin associate via their SH3 domains with a proline-rich motif found on PTP-PEST, suggesting the possibility that PTP-PEST could be a general modulator of the Cas family of proteins.
Adaptor Proteins, Signal Transducing↗
Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors.
We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa-Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 A. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.
Animals↗
[Induction of bradycardia by mibefradil in antihypertensive combination therapy].
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Adult↗
[Hemorrhagic pseudocysts and pseudoaneurysms in pancreatitis. Diagnosis and therapy].
Acute hemorrhage from pseudocysts and pseudoaneurysms is a threatening complication of chronic pancreatitis. Whilst surgical intervention still has high perioperative mortality (16.8%), transcatheter arterial embolization is becoming more frequently used for suitable cases and appears to have lower mortality (6.1%). We report on six patients treated in our unit. Four of them underwent primary surgical treatment, the other two were treated by embolisation. One of the latter patients subsequently required laparotomy for further treatment. All six patients survived. Comparing the literature covering the periods between 1951 and 1981 and between 1982 and 1996, transcatheter embolisation seems to be valuable in controlling this type of bleeding, thereby reducing mortality.
Adult↗
Repression of c-fos and c-jun gene expression is not part of AT2 receptor coupled signal transduction.
The signal transduction mechanism coupled to angiotensin AT2 receptors is still a matter of debate. Based on the findings that AT2 receptor stimulation causes inhibition of proliferation, and that other antiproliferative agents such as transforming growth factor-beta, retinoic acid, and MyoD act via repression of immediate early gene (IEG) expression, this study was aimed at elucidating whether downregulation of IEG expression is also part of the AT2 receptor coupled signaling mechanism. Stimulation of angiotensin AT2 receptors in the rat pheochromocytoma cell line PC12 W following pretreatment with growth factors was able to counteract growth factor induced proliferation but not to repress growth factor induced c-fos and c-jun expression; neither did AT2 receptor stimulation cause an induction of c-fos expression. We conclude that, in contrast to other growth-inhibiting agents, the antiproliferative effect of angiotensin II via the AT2 receptor is not mediated by repression of the immediate early genes c-fos and c-jun.
Angiotensin II↗
Diabetes--renal function--what are the special problems?
Diabetic nephropathy has become the single most important cause of endstage renal failure in most countries of the Western world. Against this background, the role of the renin-angiotensin system (RAS) and its blockade command considerable interest. In diabetic patients and in diabetic animals, the circulating components of the RAS are suppressed. Although the evidence is not completely uniform, there are indirect arguments (renal hemodynamic response to RAS blockade, AT1 receptor expression), however, which would be consistent with increased intrarenal action of angiotensin (ANG) II. There is solid evidence that ACE inhibitors effectively interfere with progression of micro-albuminuria both in IDDM and NIDDM. They also prevent progression of advanced renal failure in IDDM, while there is only preliminary evidence in this respect for NIDDM. ACE inhibitors are superior to conventional antihypertensive agents (with the possible exception of some calcium channel blockers), but such superiority is seen only when the levels of blood pressure are relatively high. In diabetic animals, treatment with ANG II receptor blockers interferes with the development of glomerular lesions. In acute and subacute studies on diabetic patients, ANG II receptor blockers reduced albuminuria (or proteinuria) more than beta-blockers. Head-on comparison of equipotent doses ACE inhibitors and ANG II receptor blockers in non-diabetic patients produced equal reductions in proteinuria. The long-term effects of ANG II receptor blockers on progression of advanced diabetic nephropathy is the object of two large international studies. The results will not be available before the year 2000.
Angiotensin Receptor Antagonists↗
Simulation of the fertilization Ca2+ wave in Xenopus laevis eggs.
In the preceding paper Fontanilla and Nuccitelli (Biophysical Journal 75:2079-2087 (1998)) present detailed measurements of the shape and speed of the fertilization Ca2+ wave in Xenopus laevis eggs. In order to help interpret their results, we develop here a computational technique based on the finite element method that allows us to carry out realistic simulations of the fertilization wave. Our simulations support the hypothesis that the physiological state of the mature egg is bistable, i.e., that its cytoplasm can accommodate two alternative physiological Ca2+ concentrations: a low concentration characteristic of the prefertilization state and a greatly elevated concentration characteristic of the state following the passage of the wave. We explore this hypothesis by assuming that the bistability is due to the release and re-uptake properties of the endoplasmic reticulum (ER) as determined by inositol trisphosphate (IP3) receptor/Ca2+ channels and sarcoendoplasmic reticulum calcium ATPase (SERCA) pumps. When combined with buffered diffusion of Ca2+ in the cytoplasm, our simulations show that inhomogeneities in the Ca2+ release properties near the plasma membrane are required to explain the temporal and spatial dependences of the shape and speed of these waves. Our results are consistent with an elevated IP3 concentration near the plasma membrane in the unfertilized egg that is augmented significantly near the site of fertilization. These gradients are essential in determining the concave shape of the Ca2+ fertilization wave front.
Animals↗
A comparison of rigid -v- video thoracoscopy in the management of chest trauma.
Between December 1, 1994 and April 1,1998, 44 thoracoscopic procedures were performed in 42 patients following chest injuries. Indications included exploration in 15, retained haemothorax in 10, continued bleeding after chest tube placement in 3, air leak in 5 and empyema in 11. Video thoracoscopy was used in 24 cases and rigid thoracoscopy in 20, including 14 patients in whom video thoracoscopy was contraindicated. There was no difference in the operative times, length of stay or incidence of complications. Two formal and 3 "mini" thoracotomies were used in the video thoracoscopy group. Three "mini" thoracotomies were required in the rigid thoracoscopy group. Rigid thoracoscopy is an effective tool that, in selected cases, increases the utility of thoracoscopy in the management of chest trauma and its complications.
Contraindications↗
BDNF regulates reelin expression and Cajal-Retzius cell development in the cerebral cortex.
Cajal-Retzius (CR) cells of the cerebral cortex express receptors for the neurotrophin brain-derived neurotrophic factor (BDNF) and downregulate expression of the extracellular matrix protein Reelin during early postnatal development, coincident with the onset of cortical BDNF expression. During this period, mice lacking BDNF have elevated levels of Reelin in CR cells. Acute BDNF stimulation of cortical neuron cultures and overexpression of BDNF in the developing brain of transgenic mice prior to the onset of endogenous production causes a profound, dose-dependent reduction of Reelin expression in CR cells. In addition, overexpression of BDNF produces gaps and heterotopias in the marginal zone and disorganization and aggregation of cortical CR cells and induces several other malformations, including aberrant cortical lamination, similar to the phenotype of reeler mutant mice, which lack Reelin. These results demonstrate a role for BDNF on cortical CR cells and identify Reelin as a direct effector of this neurotrophin during brain development.
Animals↗
Managing the uncertainties of low-level radioactive waste disposal.
The disposal of low-level radioactive waste (LLRW) entails financial and safety risks not common to most market commodities. This manifests debilitating uncertainty regarding future waste volume and disposal technology performance in the market for waste disposal services. Dealing with the publicly perceived risks of LLRW disposal increases the total cost of the technology by an order of magnitude, relative to traditional shallow land burial. Therefore, this analysis first examines five proposed disposal facility designs and quantifies the costs associated with these two important sources of uncertainty. Based upon this analysis, a marketable disposal permit mechanism is proposed and analyzed for the purpose of reducing market uncertainty and thereby facilitating a market solution to the waste disposal problem. In addition to quantifying the costs, the results illustrate the ways in which the design of a technology is influenced by its institutional environment, and vice versa.
Costs and Cost Analysis↗
HBW 023 (recombinant hirudin) for the acceleration of thrombolysis and prevention of coronary reocclusion in acute myocardial infarction: results of a dose-finding study (HIT-II) by the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte.
OBJECTIVE: To define an optimal dose of hirudin that would improve early coronary artery Thrombolysis in Myocardial Infarction grade 3 (TIMI 3) patency and prevent reocclusions in patients with acute myocardial infarction treated with front-loaded recombinant tissue-type plasminogen activator (rt-PA). METHODS: Recombinant hirudin (HBW 023) was tested in a sequential dose-escalating study as adjunct to front-loaded rt-PA in 143 patients with acute myocardial infarction. The sequential model was assigned two 'decision boundaries': it triggered an increase in dosage if the 60-min TIMI 3 flow rate in a dosage group was statistically not consistent with a target patency rate of 75%, or if the deterioration in coronary blood flow (of at least one TIMI grade, from TIMI 2 or 3, from one angiography to the next) exceeded 5%. RESULTS: The decision boundary for TIMI 3 flow grade at 60 min was crossed when 18 patients were treated with 0.1/0.06 mg/kg (bolus/infusion per hour over 48 h) r-hirudin (dosage group I), 42 patients treated with 0.2/0.1 mg/kg (dosage group II), and 83 patients with 0.4/0.15 mg/kg (dosage group III). TIMI 3 flow at 60 min was 50%, 58%, and 63% in dosage groups I-III, respectively (P = 0.15). Early, complete, and sustained patency (TIMI 3 flow at 60 min, 90 min and 48 h) were 44%, 55% and 64% (P = 0.07). Reocclusion between 90-min and 48-h angiograms or reinfarction occurred in 0 to 15, two of 36, and one of 72 patients, respectively (P = 0.5). Four patients (2.8%) died in hospital and 14 patients suffered a major bleeding event, but no intracranial bleeding was encountered. CONCLUSIONS: With increasing doses of hirudin, there was a trend towards greater early and complete patency, but no clear dose--response relationship was observed. A borderline significant effect was observed with respect to early, complete, and sustained patencies. In all groups, reocclusions or reinfarctions were rare. Neither clinical nor laboratory data predicted the imbalance in haemorrhagic events observed in a subsequent, prematurely terminated, phase III trial with hirudin and rt-PA.
Adult↗