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J Topp

Publications and source records attributed to J Topp.

9 recordsLinked to original sources
PubMed2000

Polymorphic gene regulation and interindividual variation of UDP-glucuronosyltransferase activity in human small intestine.

UDP-glucuronosyltransferases (UGTs) convert dietary constituents, drugs, and environmental mutagens to inactive hydrophilic glucuronides. Recent studies have shown that the expression of the UGT1 and UGT2 gene families is regulated in a tissue-specific fashion. Human small intestine represents a major site of resorption of dietary constituents and orally administered drugs and plays an important role in extrahepatic UGT directed metabolism. Expression of 13 UGT1A and UGT2B genes coupled with functional and catalytic analyses were studied using 18 small intestinal and 16 hepatic human tissue samples. Hepatic expression of UGT gene transcripts was without interindividual variation. In contrast, a polymorphic expression pattern of all the UGT genes was demonstrated in duodenal, jejunal, and ileal mucosa, with the exception of UGT1A10. To complement these studies, interindividual expression of UGT proteins and catalytic activities were also demonstrated. Hyodeoxycholic acid glucuronidation, catalyzed primarily by UGT2B4 and UGT2B7, showed a 7-fold interindividual variation in small intestinal duodenal samples, in contrast to limited variation in the presence of 4-methylumbelliferone, a substrate glucuronidated by most UGT1A and UGT2B gene products. Linkage of RNA expression patterns to protein abundance were also made with several mono-specific antibodies to the UGTs. These results are in contrast to a total absence of polymorphic variation in gene expression, protein abundance, and catalytic activity in liver. In addition, the small intestine exhibits considerable catalytic activity toward most of the different classes of substrates accepted for glucuronidation by the UGTs, which is supported by immunofluorescence analysis of UGT1A protein in the mucosal cell layer of the small intestine. Thus, tissue-specific and interindividual polymorphic regulation of UGT1A and UGT2B genes in small intestine is identified and implicated as molecular biological determinant contributing to interindividual prehepatic drug and xenobiotic metabolism in humans.

Blotting, Western↗
PubMed1999

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

Animals↗
PubMed1999

Harm reduction: concepts and practice. A policy discussion paper.

This paper provides an overview of the context, definition, and key features of the harm reduction approach, and provides several examples of current programs in various countries. Both licit and illicit drugs are included in these illustrations. Some of the critical issues, and the strategies needed to advance harm reduction, are discussed. [Translations are provided in the International Abstracts Section of this issue.]

Canada↗
PubMed1998

Evidence of a negative feedback system regulating the total beta-cell volume in nondiabetic rats that received pancreas transplants.

BACKGROUND: The aim of the present study was to investigate the long-term regulation of pancreatic beta-cell volume after pancreas transplantation into adult rats. METHODS: A syngeneic pancreaticoduodenal transplantation was made in normoglycemic Wistar-Furth rats. By this means, the recipients doubled their pancreatic islet volume. Nine months after transplantation, the total beta-cell volume was measured in serial pancreatic sections immunostained for insulin from both the native and transplanted pancreata, and in the native pancreas of age-matched Wistar-Furth rats that did not receive transplants. RESULTS: No changes in the volume of individual beta-cells were seen. A 50% decrease in total beta-cell volume was observed in both the native and transplanted pancreas when compared with that of age-matched controls. However, the combined beta-cell volumes of the native and transplanted pancreas in the rats that received transplants were similar to those of the native pancreas in control animals. No signs of increased apoptosis in any of the glands could be seen during the first postoperative week or after 9 months. CONCLUSIONS: These findings provide evidence of a negative feedback system, which regulates the total beta-cell volume to the levels seen in age-matched rats that did not receive transplants. The underlying mechanisms for the decreased beta-cell volume are unknown, but may involve a diminished replicatory rate of the beta-cells.

Animals↗
PubMed1998

Intubation via the LMA using a Cook retrograde intubation kit.

PURPOSE: We report two cases of difficult intubation where a laryngeal mask airway (LMA) was used and changed to a conventional endotracheal tube using a retrograde intubation set. CLINICAL FINDINGS: In two patients, following induction of anaesthesia, the trachea could not be intubated in the conventional fashion with a blade. In both patients an LMA was inserted to achieve an airway. In both patients intubation with a conventional endotracheal tube was required. A Cook Retrograde Intubation Kit and fibreoptic bronchoscope were used to change the LMA to conventional endotracheal tube without problems. CONCLUSION: The Cook retrograde intubation allows an LMA to be replaced with an endotracheal tube with an ID greater than 6 mm with a #3 or 7 mm with a #5 LMA. This technique places an exchange stylet into the airway which is superior to a conventional guidewire. This method allows the airway to be maintained until the LMA is exchanged with an endotracheal tube. Anaesthesia may be maintained and the airway instrumented without difficulty using this technique.

Adult↗
PubMed1992

Multicenter dose-finding trial for thrombolysis with urokinase preactivated pro-urokinase (TCL 598) in acute myocardial infarction. German Preactivated Pro-Urokinase Study Group.

In a multicenter dose-finding study, the thrombolytic potency of urokinase preactivated pro-urokinase was evaluated. Sixty-two patients were randomly assigned to receive 250,000 U of urokinase plus either 4.5 mega U (group I: n = 33) or 6.5 mega U (group II: n = 29) of pro-urokinase. Patency rates were 36.4% (20.4-54.9%) vs. 54.5% (36.3-71.9%) (n = 27) at 60 minutes and 55.6% (32.5-70.6%) vs. 62.1% (42.3-79.3%) at 90 min into thrombolysis (n.s.). In a third group of 12 patients treated with 500,000 U of urokinase plus 6.5 mega U of pro-urokinase patency was achieved in 33.3% (9.9-65.1%) and 41.7% (15.2-72.3%) at 60 and 90 min, respectively. Patency rates at 24 hr follow-up angiography (n = 35) were 78.6% (49.2-95.3%), 85.7% (57.2-98.2%), and 85.7% (42.1-99.6%). Coagulation analysis in 37 patients revealed similar alterations in the three treatment groups with minor decreases in fibrinogen levels, moderate drops in plasminogen and alpha-2-antiplasmin levels, and moderate increases in the concentrations of the total fibrinogen/fibrin degradation products, the differences between the groups not being significant. Bleeding complications were observed in 12.9%, 13.8%, and 25% of patients in groups I, II, and III, respectively, mainly related to catheter sites. Hence, the safety profile of urokinase preactivated pro-urokinase seems comparable to other thrombolytic regimens. Reopening of occluded coronary arteries, however, is achieved relatively slowly. Thus, in its use for thrombolysis in myocardial infarction, urokinase preactivated pro-urokinase does not seem to offer superior advantages.

Coronary Angiography↗
PubMed1990

[Incidence of residual thrombi following successful thrombolytic therapy in acute myocardial infarct and their significance for the rate of early re-occlusion. A report of a multicenter dose-finding study for thrombolytic therapy with urokinase preactivated natural prourokinase (TCL 598)].

Thrombolysis with urokinase preactivated prourokinase was performed in 74 patients. At control angiography, 90 min into thrombolysis, in 39 (52.7%) patients the infarct-related coronary artery was found patent. However, 26 out of the 39 patients (66.7%) with a patent infarct artery demonstrated angiographic signs of residual coronary thrombi. With an estimated average of 75 +/- 25% in both, patients with and without residual thrombus, the severity of the residual stenosis after thrombolysis was found to be independent from the presence of angiographic signs of residual coronary artery thrombosis. In patients with residual coronary thrombi, however, a trend towards poorer coronary perfusion was observed (50% vs 77% of the patients with prompt antegrade [TIMI grade III] perfusion [p less than 0.2]. Control angiography performed 24 to 36h after thrombolysis revealed reocclusion of the infarct artery in 26.3% of the patients with residual coronary thrombi, while none of the infarct vessels without angiographic signs of residual thrombosis had reoccluded (p less than 0.05). At follow-up angiography 17 to 23 days after thrombolysis this difference in the incidence of reocclusions had further increased to 43.8% of patients with vs 12.5% of patients without residual coronary thrombus (p less than 0.01). Thus, after thrombolysis, residual thrombotic material remaining in the infarct related vessel seems to be a major risk factor, indicating early reocclusion of the infarct artery.

Angioplasty, Balloon, Coronary↗