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J Burke

Publications and source records attributed to J Burke.

At least 55 records · Page 3Linked to original sources
PubMed1999

Safety of Neoral conversion in maintenance renal transplant patients: A one-year, double-blind study. NOVARTIS OLN-353 Study Group.

BACKGROUND: Despite the improved pharmacokinetic characteristics of Neoral, some centers have encountered difficulty with the conversion of some patients from Sandimmune to Neoral and have reported precipitation of toxicity and rejection. METHODS: We conducted a randomized, double-blind, parallel-group, multicenter prospective study of stable maintenance renal transplant patients to compare the safety and tolerability of converting from Sandimmune to Neoral (N = 132) versus continuing Sandimmune (N = 130). Patients were studied for one year. The cyclosporine (CsA) dose was adjusted as necessary to maintain site-specific trough whole blood levels. RESULTS: During the study, dose adjustments were frequent in both groups: 67% Neoral versus 65% Sandimmune patients. At study completion, the mean trough CsA levels were comparable; the dose change-from-baseline did not differ statistically between groups. Fewer Neoral (87.1%) than Sandimmune (95.4%) patients reported adverse events, and serious adverse events were comparable. Adverse events related to CsA were not more common in the Neoral group. Renal function measures also implied comparability of the two treatments. Three Neoral versus five Sandimmune patients experienced acute rejection; two Neoral versus five Sandimmune patients experienced chronic graft dysfunction. Two septic deaths occurred in the Neoral group. No grafts were lost. CONCLUSIONS: With careful monitoring, conversion of maintenance renal transplant patients to Neoral can be safely accomplished.

Adult↗
PubMed1999

CRAWview: for viewing splicing variation, gene families, and polymorphism in clusters of ESTs and full-length sequences.

MOTIVATION: DNA sequence clustering has become a valuable method in support of gene discovery and gene expression analysis. Our interest lies in leveraging the sequence diversity within clusters of expressed sequence tags (ESTs) to model gene structure for the study of gene variants that arise from, among other things, alternative mRNA splicing, polymorphism, and divergence after gene duplication, fusion, and translocation events. In previous work, CRAW was developed to discover gene variants from assembled clusters of ESTs. Most importantly, novel gene features (the differing units between gene variants, for example alternative exons, polymorphisms, transposable elements, etc.) that are specialized to tissue, disease, population, or developmental states can be identified when these tools collate DNA source information with gene variant discrimination. While the goal is complete automation of novel feature and gene variant detection, current methods are far from perfect and hence the development of effective tools for visualization and exploratory data analysis are of paramount importance in the process of sifting through candidate genes and validating targets. RESULTS: We present CRAWview, a Java based visualization extension to CRAW. Features that vary between gene forms are displayed using an automatically generated color coded index. The reporting format of CRAWview gives a brief, high level summary report to display overlap and divergence within clusters of sequences as well as the ability to 'drill down' and see detailed information concerning regions of interest. Additionally, the alignment viewing and editing capabilities of CRAWview make it possible to interactively correct frame-shifts and otherwise edit cluster assemblies. We have implemented CRAWview as a Java application across windows NT/95 and UNIX platforms. AVAILABILITY: A beta version of CRAWview will be freely available to academic users from Pangea Systems (http://www.pangeasystems.com). Contact :

Alternative Splicing↗
PubMed1999

Access to coronary artery bypass surgery by race/ethnicity and gender among patients who are appropriate for surgery.

OBJECTIVE: The study sought to determine if there were race/ethnicity or gender differences in access to coronary artery bypass graft (CABG) surgery among patients who have been designated as appropriate and as necessary for that surgery according to the RAND methodology. METHODS: RAND appropriateness and necessity criteria were used to identify a race/gender stratified sample of postangiography patients who would benefit from coronary artery bypass graft surgery. These patients were tracked for 3 months to determine if they had undergone coronary artery bypass graft surgery in New York State. Subjects were a total of 1,261 postangiography patients in eight New York hospitals in 1994 to 1996. Measures included percentages of patients for whom coronary artery bypass graft surgery was appropriate and necessary undergoing surgery by race/ethnicity and gender, as well as multivariate odds ratios for race/ethnicity and gender. RESULTS: After controlling for age, payer, number of vessels diseased, and presence of left main disease, African-American and Hispanic patients were found to be significantly less likely to undergo coronary artery bypass graft surgery than white non-Hispanic patients (respective odds ratios 0.64 and 0.60). When "necessity" was used as a criterion instead of "appropriateness," significant differences in access for African-American patients remained. The gatekeeper physician recommended surgery only 10% of the time that patients did not undergo "appropriate" coronary artery bypass graft surgery, and this percentage did not vary significantly by race/ethnicity or gender of the patient. CONCLUSIONS: Even after controlling for appropriateness and necessity for coronary artery bypass graft surgery in a prospective study, African-American patients had significant access problems in obtaining coronary artery bypass graft surgery. These problems appeared not to be related to patient refusals.

Black or African American↗
PubMed1999

d2_cluster: a validated method for clustering EST and full-length cDNAsequences.

Several efforts are under way to condense single-read expressed sequence tags (ESTs) and full-length transcript data on a large scale by means of clustering or assembly. One goal of these projects is the construction of gene indices where transcripts are partitioned into index classes (or clusters) such that they are put into the same index class if and only if they represent the same gene. Accurate gene indexing facilitates gene expression studies and inexpensive and early partial gene sequence discovery through the assembly of ESTs that are derived from genes that have yet to be positionally cloned or obtained directly through genomic sequencing. We describe d2_cluster, an agglomerative algorithm for rapidly and accurately partitioning transcript databases into index classes by clustering sequences according to minimal linkage or "transitive closure" rules. We then evaluate the relative efficiency of d2_cluster with respect to other clustering tools. UniGene is chosen for comparison because of its high quality and wide acceptance. It is shown that although d2_cluster and UniGene produce results that are between 83% and 90% identical, the joining rate of d2_cluster is between 8% and 20% greater than UniGene. Finally, we present the first published rigorous evaluation of under and over clustering (in other words, of type I and type II errors) of a sequence clustering algorithm, although the existence of highly identical gene paralogs means that care must be taken in the interpretation of the type II error. Upper bounds for these d2_cluster error rates are estimated at 0.4% and 0.8%, respectively. In other words, the sensitivity and selectivity of d2_cluster are estimated to be >99.6% and 99.2%.

Algorithms↗
PubMed1999

A comprehensive approach to clustering of expressed human gene sequence: the sequence tag alignment and consensus knowledge base.

The expressed human genome is being sequenced and analyzed by disparate groups producing disparate data. The majority of the identified coding portion is in the form of expressed sequence tags (ESTs). The need to discover exonic representation and expression forms of full-length cDNAs for each human gene is frustrated by the partial and variable quality nature of this data delivery. A highly redundant human EST data set has been processed into integrated and unified expressed transcript indices that consist of hierarchically organized human transcript consensi reflecting gene expression forms and genetic polymorphism within an index class. The expression index and its intermediate outputs include cleaned transcript sequence, expression, and alignment information and a higher fidelity subset, SANIGENE. The STACK_PACK clustering system has been applied to dbEST release 121598 (GenBank version 110). Sixty-four percent of 1,313, 103 Homo sapiens ESTs are condensed into 143,885 tissue level multiple sequence clusters; linking through clone-ID annotations produces 68,701 total assemblies, such that 81% of the original input set is captured in a STACK multiple sequence or linked cluster. Indexing of alignments by substituent EST accession allows browsing of the data structure and its cross-links to UniGene. STACK metaclusters consolidate a greater number of ESTs by a factor of 1. 86 with respect to the corresponding UniGene build. Fidelity comparison with genome reference sequence AC004106 demonstrates consensus expression clusters that reflect significantly lower spurious repeat sequence content and capture alternate splicing within a whole body index cluster and three STACK v.2.3 tissue-level clusters. Statistics of a staggered release whole body index build of STACK v.2.0 are presented.

Algorithms↗
PubMed1998

Genetic defect in N-acetylglucosaminyltransferase I gene of a ricin-resistant baby hamster kidney mutant.

The analysis of mutations associated with glycosylation-defective cell lines has the potential for identifying critical residues associated with the activities of enzymes involved in the biosynthesis of glycoconjugates. A ricin-resistant (RicR) baby hamster kidney (BHK) cell mutant, clone RicR14, has a deficiency in N-acetylglucosaminyltransferase I (GlcNAc-TI) activity and as a consequence is unable to synthesize complex and hybrid N-glycans. Here we show that RicR14 cells transfected with wild-type GlcNAc-TI regained the ability to synthesize complex N-glycans, demonstrating that the glycosylation defect of RicR14 cells is due solely to the lack of GlcNAc-TI activity. With the use of specific antibodies to GlcNAc-TI, RicR14 cells were shown to synthesize an inactive GlcNAc-TI protein that is correctly localized to the Golgi apparatus. We have cloned and sequenced the open reading frame of GlcNAc-TI from parental BHK and RicR14 cells. A comparison of several RicR14 cDNA clones with the parental BHK GlcNAc-TI sequence indicated the presence of two different RicR14 cDNA species. One contained a premature stop codon at position +81, whereas the second contained a point mutation in the catalytic domain of GlcNAc-TI resulting in the amino acid substitution Gly320-->Asp. The introduction of a Gly320-->Asp mutation into wild-type rabbit GlcNAc-TI resulted in a complete loss of activity; the GlcNAc-TI mutant was correctly localized to the Golgi, indicating that the inactive GlcNAc-TI protein was transport-competent. Gly320 is conserved in GlcNAc-TI from all species so far examined. Overall these results demonstrate that Gly320 is a critical residue for GlcNAc-TI activity.

Amino Acid Sequence↗
PubMed1998

Aflatoxin B1 and sulphobromophthalein binding to the dimeric human glutathione S-transferase A1-1: a fluorescence spectroscopic analysis.

The binding interactions between dimeric human class alpha glutathione S-transferase A1-1 (GST A1-1) and aflatoxin B1 or sulphobromophthalein (BSP) were characterised. Aflatoxin B1 binds to GST A1-1 with a stoichiometry of 1.1 mol/mol of dimeric enzyme. The binding interaction, which can be described by a hyperbolic saturation isotherm (Kd = 8+/-2 microM), does not induce major structural changes in the enzyme, nor does it inhibit enzymatic activity. The average distance between the single tryptophan residue (Trp20) of GST A1-1 and protein-bound aflatoxin B1 was calculated to be 22.7 A by means of fluorescence resonance energy transfer. The aflatoxin-binding region, according to this calculated distance, was determined to be located in the dimer interface cleft near the crystallographic two-fold axis. Hill-plot analyses suggest that a positive co-operative interaction exists between BSP and the dimeric GST A1-1 (h = 1.6+/-0.1; K' = 14+/-0.6 microM). The binding of BSP induces a conformational change in the enzyme which is accompanied by a decrease in the molecular flexibility and in the solvent-accessible properties of the enzyme's Trp20 residue. Site-directed mutagenesis of Trp20 (Trp20-->Phe) confirms that this residue is situated in the binding environment and although it is not essential for BSP binding, it is involved in the interaction. Furthermore, the structural change associated with BSP binding alters the hyperbolic character of the glutathione saturation curve. This indicates that there may also be a cooperative interaction between glutathione and BSP or that BSP binding induces asymmetric functioning of the two enzyme subunits so that they become unequal in catalytic activity.

Aflatoxin B1↗
PubMed1998

Resource costing for multinational neurologic clinical trials: methods and results.

We present the results of a multinational resource costing study for a prospective economic evaluation of a new medical technology for treatment of subarachnoid hemorrhage within a clinical trial. The study describes a framework for the collection and analysis of international resource cost data that can contribute to a consistent and accurate intercountry estimation of cost. Of the 15 countries that participated in the clinical trial, we collected cost information in the following seven: Australia, France, Germany, the UK, Italy, Spain, and Sweden. The collection of cost data in these countries was structured through the use of worksheets to provide accurate and efficient cost reporting. We converted total average costs to average variable costs and then aggregated the data to develop study unit costs. When unit costs were unavailable, we developed an index table, based on a market-basket approach, to estimate unit costs. To estimate the cost of a given procedure, the market-basket estimation process required that cost information be available for at least one country. When cost information was unavailable in all countries for a given procedure, we estimated costs using a method based on physician-work and practice-expense resource-based relative value units. Finally, we converted study unit costs to a common currency using purchasing power parity measures. Through this costing exercise we developed a set of unit costs for patient services and per diem hospital services. We conclude by discussing the implications of our costing exercise and suggest guidelines to facilitate more effective multinational costing exercises.

Australia↗
PubMed1998

Absolute bioavailability and electroencephalographic effects of conventional and extended-release formulations of venlafaxine in healthy subjects.

Venlafaxine is currently marketed for treatment of depressive disorders as a conventional tablet formulation with a twice or three times daily dosage regimen. The absolute bioavailability of the conventional (CF) and extended-release (XR) formulations and their effects on electroencephalograms (EEG) and on a visual analog scale (VAS) for nausea were assessed in a randomized, double-blind, four-way crossover, placebo-controlled study of 16 healthy young men who were given either a single oral dose of 50 mg of CF venlafaxine, 75 mg of XR venlafaxine, or an intravenous dose of 10 mg of venlafaxine, or a placebo at 1-week intervals. The absolute bioavailability of venlafaxine was between 40% and 45% and was similar for both the CF and XR formulations. Venlafaxine produced central effects of a desipramine-like antidepressant. Regardless of formulation tested, the main EEG changes were an increase in fast beta (20-30 Hz) energy, which was more pronounced over the frontotemporal regions and extended within the full beta range (16-40 Hz). Maximum effect was reached at 6 hours for the CF and reached a plateau from 10 to 24 hours for the XR formulation. A dose-proportional increase in central activity, expressed as area under the effect curve (AUE) of the beta band, was observed between the CF (50 mg) and XR (75 mg) formulations. Compared with the CF tablet, the XR formulation also produced a much less intense maximum effect and a decrease of 63% in the AUE of nausea normalized by dose. The XR formulation has the same absolute bioavailability and the same central activity as assessed by EEG, but produced less intensive nausea than CF venlafaxine. The present findings suggest that a once-daily dosage regimen should be sufficient. This was confirmed by several clinical trials in depressive patients.

Adult↗
PubMed1998

Ophthalmic abnormalities in homocystinuria: the value of screening.

PURPOSE: Homocystinuria, a genetic metabolic abnormality, eventually causes a variety of ocular and other pathologies if not treated. To evaluate the results of screening newborns for homocystinuria, we compared ophthalmic outcomes for two groups of homocystinuria patients who had been diagnosed either at birth or later than 6 weeks. METHODS AND RESULTS: Nineteen patients had been screened and diagnosed shortly after birth, with treatment instigated before 6 weeks of age (mean follow-up and age 10.8 years; median 11 years). Eight of 17 were myopic; 13 of 15 had good vision in both eyes; one had lens subluxation. The second group of 17 patients were diagnosed later than 6 weeks, often (12 patients) because of ocular problems (mean follow-up 8.3 years; mean age 19.4 years; median age 16 years). Visual function varied from 6/6 (4 patients) to less than 6/36 (4 patients); 3 eyes had no perception of light. Thirteen patients had lens subluxation or dislocation. CONCLUSION: Early diagnosis and treatment of homocystinuria is advantageous.

Adolescent↗
PubMed1998

Alternative gene form discovery and candidate gene selection from gene indexing projects.

Several efforts are under way to partition single-read expressed sequence tag (EST), as well as full-length transcript data, into large-scale gene indices, where transcripts are in common index classes if and only if they share a common progenitor gene. Accurate gene indexing facilitates gene expression studies, as well as inexpensive and early gene sequence discovery through assembly of ESTs that are derived from genes that have not been sequenced by classical methods. We extend, correct, and enhance the information obtained from index groups by splitting index classes into subclasses based on sequence dissimilarity (diversity). Two applications of this are highlighted in this report. First it is shown that our method can ameliorate the damage that artifacts, such as chimerism, inflict on index integrity. Additionally, we demonstrate how the organization imposed by an effective subpartition can greatly increase the sensitivity of gene expression studies by accounting for the existence and tissue- or pathology-specific regulation of novel gene isoforms and polymorphisms. We apply our subpartitioning treatment to the UniGene gene indexing project to measure a marked increase in information quality and abundance (in terms of assembly length and insertion/deletion error) after treatment and demonstrate cases where new levels of information concerning differential expression of alternate gene forms, such as regulated alternative splicing, are discovered. [Tables 2 and 3 can be viewed in their entirety as Online Supplements at http://www.genome.org.]

Alternative Splicing↗
PubMed1998

The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control.

OBJECTIVE: To test the hypothesis that metformin therapy, given as an adjunct to insulin therapy, improves metabolic control in insulin-treated NIDDM patients with suboptimal glycemic control. RESEARCH DESIGN AND METHODS: A total of 33 subjects with insulin-treated NIDDM were investigated; all had commenced insulin after secondary failure of antihyperglycemic agents. Two randomized double-blind placebo-controlled crossover studies were run. In study 1 (n = 19), insulin-treated subjects with suboptimal glycemic control received 12 weeks of metformin 1 g b.i.d. and 12 weeks of placebo. In study 2 (n = 14), subjects already established on adjunctive metformin/insulin therapy stopped the metformin component and received 12 weeks of metformin at their baseline dosage (range 1-2.5 g) and 12 weeks of equivalent placebo. Fasting plasma glucose, HbA1c, and serum lipids were measured at baseline and midway through and at the end of each treatment phase. The effect of 12 weeks of metformin treatment was compared with the effect of 12 weeks of placebo in each study and in both studies combined. RESULTS: In study 1, metformin treatment was associated with significant improvements in fasting plasma glucose (mean 12-week difference from placebo [95% CI]: 5.8 mmol/l [3.5-8.1], P < 0.001) and HbA1c (1.6% [0.9-2.4], P < 0.001). In study 2, metformin treatment was associated with significantly lower fasting plasma glucose (5.3 mmol/l [0.6-9.9], P = 0.029) and lower HbA1c (2.4% [1.0-3.8], P = 0.003) compared with those for placebo. Study 2 also showed metformin treatment to be associated with significantly lower total cholesterol than that for placebo (1.0 mmol/l [0.1-1.9], P = 0.032) and lower LDL cholesterol (1.0 mmol/l [0.1-1.9], P = 0.028). This significant difference in serum lipids seen in study 2 was not seen in study 1, but was present when both sets of data were combined (n = 33, mean total cholesterol difference at 12 weeks [95% CI]: 0.6 mmol/l [0.1-1.1], P = 0.015). Metformin had no significant effect on triglyceride, HDL cholesterol, weight, or blood pressure. Two subjects on metformin withdrew because of side effects. CONCLUSIONS: Metformin, when given as adjunctive therapy, was well tolerated and improved glycemic control and lipid concentrations in patients with insulin-treated NIDDM whose diabetes was poorly controlled. These improvements could be maintained over the long term.

Aged↗
PubMed1998

Fluorescence properties of autofluorescent granules generated by cultured human RPE cells.

PURPOSE: To compare the fluorescence properties of autofluorescent granules generated by retinal pigment epithelial (RPE) cells in vitro with those of the lipofuscin of RPE in vivo. METHODS: Cultured human RPE cells were maintained in basal medium for as long as 1 year, fed rod outer segments (ROS) daily for as long as 56 days, fed ROS in the presence and absence of leupeptin, or fed liposomes consisting of the major phospholipids in ROS. At different time points, cells were examined for overall fluorescence, and their fluorescence spectra were determined. In addition, chloroform-methanol extracts were examined by thin-layer chromatography and compared with those generated from RPE lipofuscin. RESULTS: Autofluorescent granules accumulated in cultured RPE cells, regardless of the presence of an exogenous substrate or the nature of the substrate. The rate of accumulation of autofluorescent granules was greatest in cells fed ROS. The autofluorescent material generated in cultured RPE cells had some spectral similarities with RPE lipofuscin but differed in solubility and chromatographic mobility of their constituent fluorophores. CONCLUSIONS. The autofluorescent granules generated by cultured RPE, even with different specific substrates, differ from lipofuscin granules in vivo, suggesting that additional properties of RPE cells or of the materials they phagocytose are required to produce autofluorescent materials with the characteristics of lipofuscin.

Aged↗
PubMed1997

Epidermal growth factor activates protein kinase C in the human endometrial cancer cell line HEC-1-A.

Previous studies from this laboratory have shown that epidermal growth factor (EGF) and the tumor promoter, phorbol myristate acetate (PMA), are mitogenic in the endometrial cancer cell line HEC-1-A. Since the effects of EGF have been shown to be mediated by the protein kinase C (PKC) pathway transduction system, we examined the possibility that the EGF-responsive signal in the endometrial cancer cell line HEC-1-A involves protein kinase C activation. HEC-1-A cells were grown to confluency in 100-mm dishes and maintained in a serum-free medium for 24 hr prior to treatment. The cells were treated with EGF at varying time intervals (0.25 to 60 min) and concentrations (0.1 to 200 ng/ml). The cells were then lysed, homogenized, and centrifuged at 105,000g for 1 hr at 4 degrees C. The supernatant was chromatographed on DEAE-Sephacel columns. The membranous pellet was resuspended in 5 ml of lysis buffer containing 1% Nonidet P-40 and also chromatographed on DEAE-Sephacel columns separately. The eluates were collected and assayed for protein kinase C activity by determining the amount of 32P transferred from [gamma-32P]ATP onto histones in the presence of the phospholipids, phosphatidylserine, and diolein. Our results show that the cytoplasmic and membrane fraction of the HEC-1-A cell line contained phosphotransferase activity which displayed kinetic characteristics typical of the protein kinase C enzyme. The optimal incubation time for protein kinase C activation in the cytosol by EGF was 5 min (30-fold stimulation). The protein kinase C activity was increased when the cell lines were incubated with increasing concentrations of EGF. Enzyme saturation was seen at a concentration of 10 ng/ml of EGF (4.5-fold stimulation). Western blot analysis confirmed the presence of the PKC enzyme in the cytosol and membranes of our cancer cell line. These results suggest that EGF, at least partially, exerts its effects on the endometrial adenocarcinoma cell line by activating protein kinase C through increased breakdown of phosphatidyl inositol (PI). The PI cascade appears to be an important signal transduction system mediating the growth stimulatory effects of EGF on endometrial carcinoma.

Blotting, Western↗
PubMed1997

Sulphur hexafluoride in the treatment of flat anterior chamber following trabeculectomy.

The efficacy and side effects of sulphur hexafluoride (SF6) in the reformation of the flat anterior chamber (AC) after standard trabeculectomies were studied. Ten patients with lenticulocorneal touch following trabeculectomy were enrolled. All had water-tight conjunctival wounds with overflowing fistulas. In 5, one to four surgical attempts to reform the AC were unsuccessful. Two to seven days after trabeculectomy, the AC was reformed by a single injection of SF6/air mixture (20-40%). Gas was injected through the limbus at 3 or 9 o'clock. The AC remained deep after absorption of the gas in 2-7 days. All patients had stromal oedema in the first 4 days. This resolved and specular microscopy did not show any abnormality. After a mean follow-up of 2.5 years, all had normal intraocular pressure, 3 with one topical antiglaucoma treatment. Three patients developed cataracts before and 3 after reformation of the AC. The latter 3 were not anterior capsular cataracts as induced by gases. SF6/air mixture (20-40%) is inert and kind to the cornea and, as it is absorbed in less than 7 days, it exerts minimal damage to the crystalline lens. It is effective in the reformation of flat ACs.

Aged↗
PubMed1997

Prepulse effects on the photic eyeblink reflex: evidence for startle-dazzle theory.

Weak visual prestimulation effects on the early (R50, 50-80 ms) and late (R80, 80-200 ms) components of the eyeblink response to bright light flashes were studied in 16 normal individuals. At a lead time of 120 ms, R50 was inhibited relative to no-prepulse control trials, whereas R80 was facilitated. According to the proposed startle-dazzle theory, luminance onset transients trigger an initial response, R50, that is functionally related to startle. Sustained stimulation then activates prolonged eyelid (R80) and pupil responses, which serve to minimize retinal bleaching. Although the sensitivity of the photic blink reflex to attention is controversial, R50 latency showed a pattern suggestive of inhibition of return (Posner & Cohen, 1984, Attention and performance, Vol. X, pp. 531-556, Hillsdale, NJ: Erlbaum). Analyses in a patient with unilateral occipital lobe damage supported previous evidence that inhibition by a visual prepulse requires neocortex, but facilitation does not.

Adult↗