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Biomedical subjects

R J Lee

Publications and source records attributed to R J Lee.

At least 19 recordsLinked to original sources
PubMed2003

Twenty year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses.

OBJECTIVE: To compare survival and outcome in patients receiving a mechanical or bioprosthetic heart valve prosthesis. DESIGN: Randomised prospective trial. SETTING: Tertiary cardiac centre. PATIENTS: Between 1975 and 1979, patients were randomised to receive either a Bjork-Shiley or a porcine prostheses. The mitral valve was replaced in 261 patients, the aortic in 211, and both valves in 61 patients. Follow up now averages 20 years. MAIN OUTCOME MEASURES: Death, reoperation, bleeding, embolism, and endocarditis. RESULTS: After 20 years there was no difference in survival (Bjork-Shiley v porcine prosthesis (mean (SEM)): 25.0 (2.7)% v 22.6 (2.7)%, log rank test p = 0.39). Reoperation for valve failure was undertaken in 91 patients with porcine prostheses and in 22 with Bjork-Shiley prostheses. An analysis combining death and reoperation as end points confirmed that Bjork-Shiley patients had improved survival with the original prosthesis intact (23.5 (2.6)% v 6.7 (1.6)%, log rank test p < 0.0001); this difference became apparent after 8-10 years in patients undergoing mitral valve replacement, and after 12-14 years in those undergoing aortic valve replacement. Major bleeding was more common in Bjork-Shiley patients (40.7 (5.4)% v 27.9 (8.4)% after 20 years, p = 0.008), but there was no significant difference in major embolism or endocarditis. CONCLUSIONS: Survival with an intact valve is better among patients with the Bjork-Shiley spherical tilting disc prosthesis than with a porcine prosthesis but there is an attendant increased risk of bleeding.

Animals↗
PubMed2003

Environmental factors influencing the microbiological contamination of commercially harvested shellfish.

Filter-feeding bivalve molluscs (such as oysters, clams, mussels and cockles) can concentrate contaminants from the water column. The extent of faecal contamination in shellfish is usually estimated by determining the concentration of faecal coliforms and/or Escherichia coli. Three sample points in each of three geographically separate commercial shellfisheries were selected for analysis for the effect of season, spring/neap and high/low tidal cycles, rainfall and wind direction on the results of routine E. coli monitoring. General linear modelling was used for the analyses. The principle factors affecting the contamination of shellfisheries were season, high/low tidal cycle and rainfall. The effects varied between harvesting areas and between individual sampling points within harvesting areas. Undertaking such analyses for all harvesting areas would contribute to the management of monitoring programmes and assist in the evaluation of potentially contaminating sources, such as sewage discharges. The type of analyses undertaken on E. coli monitoring data would also be pertinent for the analysis of putative viral indicators, such as F+ coliphage, and could be extended to data on bacterial and viral pathogens.

Animals↗
PubMed2002

The time from diagnostic excision biopsy to wide local excision for primary cutaneous malignant melanoma may not affect patient survival.

BACKGROUND: The surgical management of primary cutaneous malignant melanoma usually involves an excision biopsy of the suspected lesion followed by wide local excision. No study has addressed whether a delay between these two surgical procedures influences patient outcome. OBJECTIVES: To determine if the surgical interval (SI) between the diagnostic excision biopsy and wide local excision for primary cutaneous malignant melanoma affects recurrence or survival outcome. METHODS: A cohort of 986 patients who had a diagnostic excision biopsy followed by wide local excision was identified from those registered on a specialist database that records the clinicopathological features, surgical treatment and follow-up information of all patients with malignant melanoma in Scotland. The cohort was divided into five arbitrary groups determined by the length of the SI as follows:< or =14 days, 15-28 days, 29-42 days, 43-91 days and > or = 92 days. Overall survival, disease-free survival and recurrence-free interval between the groups were compared univariately and multivariately. RESULTS: The mean age at excision biopsy was 47.4 years and the median period of follow-up was 5 years (range 27 days to 20.7 years). The median SI was 30 days (range 1-468 days). The SI was: (i)< or =14 days for 130 (13%); (ii) 15-28 days for 320 (33%); (iii) 29-42 days for 262 (27%); (iv) 43-91 days for 251 (25%); and (v) > or = 92 days for 23 (2%) patients. The latter group was older, had thinner melanomas, a higher percentage of lesions on the head and neck, fewer superficial spreading malignant melanomas and ulceration present less often compared with patients treated earlier. Univariately, there was no significant difference in overall survival (P = 0.60) or disease-free survival (P = 0.24) between the groups. Although there was a statistically significant difference in the percentage of recurrence-free patients between the groups (P = 0.011), the better recurrence-free rates occurred in the 29-42 and 43-91 day groups. After adjusting for age, sex, tumour thickness, site, histology, ulceration and mitotic activity using Cox's proportional hazards model, there was no statistically significant difference in overall survival, disease-free survival and recurrence-free percentages between the surgical groups (P = 0.88, P = 0.44 and P = 0.084, respectively). CONCLUSIONS: There was no evidence that survival outcome or recurrence was related to the time interval between the diagnostic excision biopsy and wide local excision of melanoma.

Adult↗
PubMed2001

Efficient gene delivery via non-covalent complexes of folic acid and polyethylenimine.

Polyethylenimine (PEI) is a cationic polymer capable of delivering DNA molecules into cultured mammalian cells as charge complexes. The application of PEI polyplexes in gene therapy, however, is hampered by the sensitivity of its transfection activity to the presence of serum. We found that folic acid, in a variety of cell lines, significantly enhanced PEI-mediated transfection activity in the presence of serum, whether the folic acid was added during or after PEI/DNA polyplex formation. The increase in activity could not be produced with other anionic compounds such as cholic acid, citric acid, EDTA, or glutamic acid. This novel formulation provides a reliable, low-cost, and highly efficient method for delivery of genes and may have applications in gene therapy.

DNA↗
PubMed2001

Electrophysiological effects of ibutilide in patients with accessory pathways.

BACKGROUND: Atrial fibrillation (AF) may cause life-threatening ventricular arrhythmias in patients with Wolff-Parkinson-White syndrome. We prospectively evaluated the effects of ibutilide on the conduction system in patients with accessory pathways (AP). METHODS AND RESULTS: In part I, we gave ibutilide to 22 patients (18 men, 31+/-13 years of age) who had AF during electrophysiology study, including 6 pediatric patients </=18 years of age. Ibutilide terminated AF in 21 of 22 patients (95%) during or 8+/-5 minutes after infusion and prolonged the shortest preexcited R-R interval during AF. Successful ablation was performed in all patients. In part II, ibutilide was given to 18 patients (14 men, 28+/-21 years) to assess its effects on the AP and conduction system. Ibutilide prolonged the antegrade atrioventricular node effective refractory period (ERP) (from 252+/-60 to 303+/-70 ms; P<0.02). Ibutilide caused transient loss of the delta wave in 1 patient and abolished inducible tachycardia in 2 patients, although retrograde mapping still allowed for successful AP ablation. The antegrade AP ERP prolonged from 275+/-40 to 320+/-60 ms (P<0.01), as did the antegrade AP block cycle length; the retrograde AP ERP and block cycle length similarly prolonged with ibutilide. The relative and effective refractory period of the His-Purkinje system increased in 61% of patients after ibutilide. There were no adverse side effects. CONCLUSIONS: We report the use of ibutilide in terminating AP-mediated AF, including the first report in the pediatric population. Ibutilide prolonged refractoriness of the atrioventricular node, His-Purkinje system, and AP.

Adolescent↗
PubMed2001

Overcoming the signaling defect of Lyn-sequestering, signal-curtailing FcepsilonRI dimers: aggregated dimers can dissociate from Lyn and form signaling complexes with Syk.

Clustering the tetrameric (alphabetagamma(2)) IgE receptor, FcepsilonRI, on basophils and mast cells activates the Src-family tyrosine kinase, Lyn, which phosphorylates FcepsilonRI beta and gamma subunit tyrosines, creating binding sites for the recruitment and activation of Syk. We reported previously that FcepsilonRI dimers formed by a particular anti-FcepsilonRI alpha mAb (H10) initiate signaling through Lyn activation and FcepsilonRI subunit phosphorylation, but cause only modest activation of Syk and little Ca(2+) mobilization and secretion. Curtailed signaling was linked to the formation of unusual, detergent-resistant complexes between Lyn and phosphorylated receptor subunits. Here, we show that H10-FcepsilonRI multimers, induced by adding F(ab')(2) of goat anti-mouse IgG to H10-treated cells, support strong Ca(2+) mobilization and secretion. Accompanying the recovery of signaling, H10-FcepsilonRI multimers do not form stable complexes with Lyn and do support the phosphorylation of Syk and phospholipase Cgamma2. Immunogold electron microscopy showed that H10-FcepsilonRI dimers colocalize preferentially with Lyn and are rarely within the osmiophilic "signaling domains" that accumulate FcepsilonRI and Syk in Ag-treated cells. In contrast, H10-FcepsilonRI multimers frequently colocalize with Syk within osmiophilic patches. In sucrose gradient centrifugation analyses of detergent-extracted cells, H10-treated cells show a more complete redistribution of FcepsilonRI beta from heavy (detergent-soluble) to light (Lyn-enriched, detergent-resistant) fractions than cells activated with FcepsilonRI multimers. We hypothesize that restraints imposed by the particular orientation of H10-FcepsilonRI dimers traps them in signal-initiating Lyn microdomains, and that converting the dimers to multimers permits receptors to dissociate from Lyn and redistribute to separate membrane domains that support Syk-dependent signal propagation.

Animals↗
PubMed2001

Atypical right atrial flutter patterns.

BACKGROUND: The purpose of our study was to define the incidence and mechanisms of atypical right atrial flutter. METHODS AND RESULTS: A total of 28 (8%) of 372 consecutive patients with atrial flutter (AFL) had 36 episodes of sustained atypical right AFL. Among 24 (67%) of 36 episodes of lower loop reentry (LLR), 13 (54%) of 24 episodes had early breakthrough at the lower lateral tricuspid annulus, whereas 11 (46%) of 24 episodes had early breakthrough at the high lateral tricuspid annulus, and 9 (38%) of 24 episodes showed multiple annular breaks. Bidirectional isthmus block resulted in elimination of LLR. A pattern of posterior breakthrough from the eustachian ridge to the septum was observed in 4 (14%) of 28 patients. Upper loop reentry was observed in 8 (22%) of 36 episodes and was defined as showing a clockwise orientation with early annular break and wave-front collision over the isthmus. Two patients had atypical right AFL around low voltage areas ("scars") in the posterolateral right atrium. CONCLUSIONS: Atypical right AFL is most commonly associated with an isthmus-dependent mechanism (ie, LLR or subeustachian isthmus breaks). Non-isthmus-dependent circuits include upper loop reentry or scar-related circuits.

Aged↗
PubMed2001

Risk factors for nodal recurrence after lymphadenectomy for melanoma.

BACKGROUND: The risk and outcome of regional failure after elective and therapeutic lymph node dissection (ELND/TLND) for microscopically and macroscopically involved lymph nodes without adjuvant radiotherapy were evaluated. METHODS: Retrospective melanoma database review of 338 patients (ELND 85, TLND 253) from 1970 to 1996 with pathologically involved lymph nodes. RESULTS: Regional recurrence occurred in 14% of patients treated with ELND (n = 12) and 28% of patients treated with TLND (n = 72; P = .009). Risk factors associated with nodal recurrence were advanced age, primary lesion in the head and neck region, depth of the primary lesion, number of involved lymph nodes, and extracapsular extension (ECE). For each nodal basin, the ELND group had a lower incidence of recurrence than the TLND group. The TLND group had larger lymph nodes, greater number of involved lymph nodes, and a higher incidence of ECE. The 10-year disease-specific survival was 51% vs. 30% for ELND and TLND, respectively (P = .0005). Nodal basin failure was predictive of distant metastasis, with 87% developing distant disease compared with 54% of patients without nodal recurrence (P < .0001). Of six patients who underwent a second dissection after isolated nodal recurrence, five patients have had a median disease-free interval of 79 months. CONCLUSIONS: After ELND or TLND, patients who have a large tumor burden (thick primary melanoma, multiply involved lymph nodes, ECE), advanced age, and a primary lesion located in the head and neck have a significantly increased likelihood of relapse and a decreased survival. Few patients present with an isolated nodal recurrence, but the majority can be salvaged by a second dissection.

Female↗
PubMed2001

Malignant fibrous histiocytoma: an institutional review.

BACKGROUND: A thorough understanding of malignant fibrous histiocytoma (MFH), the most common subtype of soft tissue sarcoma, will lead to improved histologic-specific protocols. METHODS: 126 patients with histologically confirmed MFH were analyzed. The median follow-up was 42 months (range 1-233 months). RESULTS: Overall survival was 58% at 5 years and 38% at 10 years. Grade significantly influenced prognosis, with 10-year survival of 90%, 60%, and 20% for low, intermediate, and high grade tumors, respectively (p = 0.0007). Distant metastases at initial presentation (p = 0.0002) and size of the primary tumor (p = 0.0007) influenced outcome. Neither anatomic site nor depth of the primary tumor were significant prognostic factors. Positive microscopic margins were associated with a decreased disease-free survival (p = 0.006). CONCLUSIONS: Tumor grade, size, and distant metastases at initial presentation remain the most important prognostic factors for MFH. Resection with negative microscopic margins decreased the incidence of local recurrence.

Disease-Free Survival↗
PubMed2001

Effects of different durations of pretreatment with losartan on myocardial infarct size, endothelial function, and vascular endothelial growth factor.

A previous study by our group showed that 10 weeks of pretreatment with losartan reduced myocardial infarct size and arrhythmias in a rat model of ischaemia-reperfusion. However, the effect of a differing time course of pretreatment has not been investigated. 104 Sprague-Dawley rats were randomised to four groups: a control, and three treatment groups in which losartan (40 mg/kg/day) was administered in drinking water for one day, one week, and four weeks respectively. After different durations of pretreatment, the rats were subjected to 17 minutes of left coronary artery occlusion and 120 minutes of reperfusion. Haemodynamic variables were not significantly different between the four groups. Myocardial infarct size was unchanged after one day and one week of pretreatment (52+/-7, 57+/-6% vs.control 55+/-3%), but was significantly reduced by four weeks of pretreatment with losartan (38+/-6, p<0.05). Endothelial-dependent vasorelaxation was significantly increased by four weeks of pretreatment (-81+/-4 vs.-62+7%, p<0.05). As an indicator of ischaemia, vascular endothelial growth factor (VEGF) levels in ischaemic myocardium were decreased after one and four weeks of pretreatment (0.75+/-0.05, 0.58+/-0.10 vs. 1.0, p<0.05,0.01, respectively). In conclusion, losartan has time-dependent cardiovascular protective effects. Four weeks of pretreatment with losartan decreased infarct size and VEGF, and improved endothelial dysfunction.

Angiotensin II↗
PubMed2001

Development of semi-empirical model for radiochemical reactions.

A mathematical model, which represents the radio-chemical reactions in water, was developed to study the effect of the radio-chemical products on cell killing. The five differential equations were solved using dose rate equation and cell survival as a function of dose was computed. The known chemical rate constants were taken from the literature and unknown constants were determined by curve fitting to an experimental data. Sensitivity studies were performed by varying the rate constants and showed that the yield of H-radical had little effect whereas the change in concentration of OH-radical and direct interaction resulted in significant change on cell survival. The sensitivity studies showed good agreement with the observed effects. In conclusion, we developed a mathematical model that could be used as a means for the estimation of radiation damage.

Cell Survival↗
PubMed2000

Peroxycarbenium-mediated C-C bond formation: applications to the synthesis of hydroperoxides and peroxides.

The Lewis acid-mediated reaction of alkene nucleophiles with peroxyacetals provides an effective route for the synthesis of homologated peroxides and hydroperoxides. In the presence of Lewis acids such as TiCl(4), SnCl(4), and trimethylsilyl triflate, peroxyacetals and peroxyketals undergo reaction with allyltrimethylsilane, silyl enol ethers, and silyl ketene acetals to afford homoallyl peroxides, 3-peroxyketones, and 3-peroxyalkanoates, respectively. Reactions of peroxyacetals are Lewis acid dependent; TiCl(4) promotes formation of ethers while SnCl(4) and trimethylsilyl triflate promote formation of peroxides. Lewis acid-promoted reactions of silylated hydroperoxyacetals furnish silylated hydroperoxides, which can be deprotected to homologated hydroperoxides. Hydroperoxyketals undergo Lewis acid-mediated allylation to furnish 1,2-dioxolanes via attack of hydroperoxide on the intermediate carbocation. Lewis acid-mediated cyclization of unsaturated peroxyacetals furnishes 1,2-dioxanes, 1,2-dioxepanes, and 1,2-dioxacanes through 6-endo/exo, 7-endo/endo, and 8-endo/endo pathways. The corresponding reactions involving 6-endo/endo and 5-endo/exo pathways were unsuccessful.

Carbon↗
PubMed2000

VEGF gene delivery to myocardium: deleterious effects of unregulated expression.

BACKGROUND: Vascular endothelial growth factor (VEGF) is being investigated for therapeutic angiogenesis in ischemic myocardium. Primarily, transient delivery systems have been tested. The goal of this study was to investigate the effects of continuous expression of VEGF in myocardium by use of myoblast-mediated delivery. METHODS AND RESULTS: Primary murine myoblasts (5 x 10(5) cells in 10 microL of PBS with 0.5% BSA) expressing both the murine VEGF gene and the beta-galactosidase (beta-gal) gene from a retroviral promoter were implanted in the ventricular wall of immunodeficient mice (n=11) via a subdiaphragmatic approach. Control immunodeficient mice (n=12) were injected with the same number of myoblasts expressing only the beta-gal gene. Between days 14 and 16, surviving mice were euthanized and the hearts processed for histology. In the experimental group, 11 of 11 mice demonstrated failure to thrive by day 13; 5 deaths occurred between days 8 and 15. There were no complications in the control mice. Histochemistry documented successful implantation of myoblasts (positive beta-gal reaction product) in 6 of 6 surviving experimental mice and 12 of 12 controls. Histology disclosed intramural vascular tumors resembling hemangiomas in the VEGF-myoblast-injected myocardium in 6 of 6 surviving mice. beta-Gal-expressing cells were present at the site of the vascular tumors. Immunohistochemistry localized abundant endothelial nitric oxide synthase and CD31 (platelet and endothelial cell adhesion molecule) within the lesion, consistent with the presence of endothelial cells. CONCLUSIONS: In this model, unregulated continuous expression of VEGF is associated with (1) a high rate of failure to thrive/death and (2) formation of endothelial cell-derived intramural vascular tumors in the implantation site. These results underscore the importance of regulating VEGF expression for therapeutic angiogenesis.

Animals↗
PubMed2000

Novel transcripts of fibroblast growth factor receptor 3 reveal aberrant splicing and activation of cryptic splice sequences in colorectal cancer.

A nested reverse transcription-PCR analysis of FGFR3 from human colorectal carcinomas revealed novel mutant transcripts caused by aberrant splicing and activation of cryptic splice sequences. Two aberrantly spliced transcripts were detected with high frequency in 50% of 36 primary tumors and in 60% of 10 human colorectal cancer cell lines. Most transcripts used normal splice sites but skipped or included exons 8 and 9. Two mutant transcripts arose from cryptic splice donor sites in exon 7 that spliced to exon 10. The predicted translation products would exhibit frameshifts and a premature termination codon in exon 10. We propose that dysregulation of mRNA splicing frequently generates an aberrant FGFR3 transcript that may confer a selectable advantage on clones of cells in colorectal tumorigenesis.

Alternative Splicing↗
PubMed2000

Involvement of tail domains in regulation of Dictyostelium myosin II.

The actin-dependent ATPase activity of Dictyostelium myosin II filaments is regulated by phosphorylation of the regulatory light chain. Four deletion mutant myosins which lack different parts of subfragment 2 (S2) showed phosphorylation-independent elevations in their activities. Phosphorylation-independent elevation in the activity was also achieved by a double point mutation to replace conserved Glu932 and Glu933 in S2 with Lys. These results suggested that inhibitory interactions involving the head and S2 are required for efficient regulation. Regulation of wild-type myosin was not affected by copolymerization with a S2 deletion mutant myosin in the same filaments. Furthermore, the activity linearly correlated with the fraction of phosphorylated molecules in wild-type filaments. These latter two results suggest that the inhibitory head-tail interactions are primarily intramolecular.

Adenosine Triphosphatases↗
PubMed2000

Targeted drug delivery via the folate receptor.

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including their fragments and derivatives, have been evaluated for tumor imaging and immunotherapy clinically and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the folate receptor, retains its receptor binding properties when derivatized via its gamma-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the folate receptor. This second strategy has been successfully applied in vitro for the receptor-specific delivery of protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, gamma-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in folate receptor-positive animal tumor models. The small size, convenient availability, simple conjugation chemistry, and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.

Animals↗