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Biomedical subjects

R J Lee

Publications and source records attributed to R J Lee.

At least 127 records · Page 7Linked to original sources
PubMed1995

Action of diphenylamine carboxylate derivatives, a family of non-steroidal anti-inflammatory drugs, on [Ca2+]i and Ca(2+)-activated channels in neurons.

Ca(2+)-activated channels, including Ca(2+)-activated non-selective (CAN) channels and Ca(2+)-activated Cl- channels play important roles in regulating the electrical activity of neurons. No blockers of neuronal CAN channels have been previously reported. We used 2-electrode voltage clamping to measure membrane currents and fura-2 fluorescence imaging to measure [Ca2+]i in molluscan neurons. We show that the diphenylamine carboxylate derivative flufenamate (FFA), but not mefenamate or the parent compound, cause a transient increase in ICAN and a slow outward current, and a maintained increase in [Ca2+]i. We interpret this as a FFA-dependent release of Ca2+ from intracellular stores and Ca2+ influx, [Ca2+]i-dependent activation of the CAN and slow outward currents, and slow FFA-dependent channel block.

Animals↗
PubMed1995

Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol.

Antisense oligodeoxyribonucleotides targeted to the epidermal growth factor (EGF) receptor were encapsulated into liposomes linked to folate via a polyethylene glycol spacer (folate-PEG-liposomes) and efficiently delivered into cultured KB cells via folate receptor-mediated endocytosis. The oligonucleotides were a phosphodiester 15-mer antisense to the EGF receptor (EGFR) gene stop codon (AEGFR2), the same sequence with three phosphorothioate linkages at each terminus (AEGFR2S), a randomized 15-mer control of similar base composition to AEGFR2 (RC15), a 14-mer control derived from a symmetrized Escherichia coli lac operator (LACM), and the 5'-fluorescein-labeled homologs of several of the above. Cellular uptake of AEGFR2 encapsulated in folate-PEG-liposomes was nine times higher than AEGFR2 encapsulated in nontargeted liposomes and 16 times higher than unencapsulated AEGFR2. Treatment of KB cells with AEGFR2 in folate-PEG-liposomes resulted in growth inhibition and significant morphological changes. Curiously, AEGFR2 and AEGFR2S encapsulated in folate-PEG-liposomes exhibited virtually identical growth inhibitory effects, reducing KB cell proliferation by > 90% 48 hr after the cells were treated for 4 hr with 3 microM oligonucleotide. Free AEGFR2 caused almost no growth inhibition, whereas free AEGFR2S was only one-fifth as potent as the folate-PEG-liposome-encapsulated oligonucleotide. Growth inhibition of the oligonucleotide-treated cells was probably due to reduced EGFR expression because indirect immunofluorescence staining of the cells with a monoclonal antibody against the EGFR showed an almost quantitative reduction of the EGFR in cells treated with folate-PEG-liposome-entrapped AEGFR2. These results suggest that antisense oligonucleotide encapsulation in folate-PEG-liposomes promise efficient and tumor-specific delivery and that phosphorothioate oligonucleotides appear to offer no major advantage over native phosphodiester DNA when delivered by this route.

Base Sequence↗
PubMed1995

Distinct functions of the Fc epsilon R1 gamma and beta subunits in the control of Fc epsilon R1-mediated tyrosine kinase activation and signaling responses in RBL-2H3 mast cells.

In RBL-2H3 rat tumor mast cells, cross-linking the high affinity IgE receptor, Fc epsilon R1, activates the protein-tyrosine kinases Lyn and Syk and initiates a series of responses including protein-tyrosine phosphorylation, inositol 1,4,5-trisphosphate synthesis, Ca2+ mobilization, secretion, membrane ruffling, and actin plaque assembly. The development of chimeric receptors containing cytoplasmic domains of individual subunits of the heterotrimeric (alpha beta gamma 2) Fc epsilon R1 has simplified analyses of early signaling events in RBL-2H3 cells. Here, RBL-2H3 cells were transfected with cDNAs encoding the extracellular and transmembrane domains of the interleukin-2 receptor alpha subunit (the Tac antigen) joined to the C-terminal cytoplasmic domains of the Fc epsilon R1 gamma and beta subunits (TT gamma and TT beta). Both sequences contain tyrosine activation motifs implicated in antigen receptor signal transduction. TT gamma and TT beta are expressed independently of the native Fc epsilon R1, as demonstrated by the ability of Tac cross-linking agents to trigger the clustering and internalization through coated pits of both chimeric receptors without co-clustering the Fc epsilon R1. A full range of signaling activities is induced by TT gamma cross-linking; the TT gamma-induced responses are slower and, except for Lyn activation, smaller than the Fc epsilon R1-induced responses. In striking contrast, TT beta cross-linking elicits no tyrosine phosphorylation or signaling responses, it impairs basal activities measured in secretion and anti-PY (anti-phosphotyrosine antibody) immune complex kinase assays, and it antagonizes Fc epsilon R1-induced Lyn and Syk activation, protein-tyrosine phosphorylation, and signaling responses. We hypothesize that the isolated beta subunit binds a specific kinase or coupling protein(s) required for signaling activity, sequestering it from the signal-transducing gamma subunit. Binding the same kinase or coupling protein to the beta subunit of the intact Fc epsilon R1 may serve instead to present it to the adjacent gamma subunit, resulting in enhanced kinase activation and signaling responses.

Animals↗
PubMed1995

Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro.

Receptors for the vitamin folic acid are frequently overexpressed on epithelial cancer cells. To examine whether this overexpression might be exploited to specifically deliver liposome-encapsulated drug molecules in vitro, folate-targeted liposomes were prepared by incorporating 0.1 mol% of a folate-polyethyleneglycol-distearoylphatidylethanolamine (folate-PEG-DSPE) construct into the lipid bilayer, and were loaded with doxorubicin (DOX), an anti-cancer drug. Uptake of folate-PEG-liposomal DOX by KB cells was 45-fold higher than that of non-targeted liposomal DOX, and 1.6-times higher than that of free DOX, while the cytotoxicity was 86 and 2.7-times higher, respectively. Folate-targeting is fully compatible with PEG-coating of the liposomes, since incorporation of 4 mol% PEG2000-DSPE does not reduce the uptake or cytotoxicity of folate-PEG-liposomal DOX. Uptake of folate-PEG-liposomes was inhibited by 1 mM free folic acid but was unaffected by physiological concentrations of folate. In HeLa/WI38 co-cultures, folate-PEG-liposomes encapsulating calcein, a fluorescent dye, were found to be almost exclusively internalized by the HeLa cells which overexpress the folate receptors. We suggest that folate targeting constitutes a possible mechanism for improving the specificity of PEG-coated liposomes for cancer cells.

Biological Transport↗
PubMed1995

Evaluation of ambient asbestos concentrations in buildings following the Loma Prieta earthquake.

On October 17, 1989, an earthquake struck central, coastal California including San Francisco and the Bay Area, damaging many buildings. Because of concern over the possible exposure to asbestos in the damaged buildings, building owners/managers hired several Bay Area industrial hygiene firms to collect air samples in suspect buildings. RJ Lee Group analyzed a total of 419 air samples from 55 buildings (25 school, 3 university, 20 commercial, 5 public, and 2 residential buildings) using transmission electron microscopy and has compiled the results. The data from each building were averaged and grouped accordingly into three classifications: indoor buildings, buildings with asbestos abatement in progress at the time of the earthquake, and buildings where sampling was performed to monitor clean-up of debris. Several buildings were sampled on more than 1 day. The results indicate that asbestos levels differed little from outdoor levels, even immediately after the earthquake. Exceptions to this were samples collected in the vicinity of debris clean-up and in buildings undergoing abatement which were higher than the indoor or outdoor samples. However, these samples generally had concentrations below the AHERA clearance levels and all were well below the OSHA action limit.

Air Pollutants↗
PubMed1995

Roles for Ca2+ stores release and two Ca2+ influx pathways in the Fc epsilon R1-activated Ca2+ responses of RBL-2H3 mast cells.

Cross-linking the high affinity IgE receptor, Fc epsilon R1, with multivalent antigen induces inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-dependent release of intracellular Ca2+ stores, Ca2+ influx, and secretion of inflammatory mediators from RBL-2H3 mast cells. Here, fluorescence ratio imaging microscopy was used to characterize the antigen-induced Ca2+ responses of single fura-2-loaded RBL-2H3 cells in the presence and absence of extracellular Ca2+ (Ca2+o). As antigen concentration increases toward the optimum for secretion, more cells show a Ca2+ spike or an abrupt increase in [Ca2+]i and the lag time to onset of the response decreases both in the presence and the absence of Ca2+o. When Ca2+o is absent, fewer cells respond to low antigen and the lag times to response are longer than those measured in the presence of Ca2+o, indicating that Ca2+o contributes to Ca2+ stores release. Ins(1,4,5)P3 production is not impaired by the removal of Ca2+o, suggesting that extracellular Ca2+ influences Ca2+ stores release via an effect on the Ins(1,4,5)P3 receptor. Stimulation with low concentrations of antigen can lead, only in the presence of Ca2+o, to a small, gradual increase in [Ca2+]i before the abrupt spike response that indicates store release. We propose that this small, initial [Ca2+]i increase is due to receptor-activated Ca2+ influx that precedes and may facilitate Ca2+ stores release. A mechanism for capacitative Ca2+ entry also exists in RBL-2H3 cells. Our data suggest that a previously undescribed response to Fc epsilon R1 cross-linking, inhibition of Ca2+ stores refilling, may be involved in activating capacitative Ca2+ entry in antigen-stimulated RBL-2H3 cells, thus providing the elevated [Ca2+]i required for optimal secretion. The existence of both capacitative entry and Ca2+ influx that can precede Ca2+ release from intracellular stores suggests that at least two mechanisms of stimulated Ca2+ influx are present in RBL-2H3 cells.

Animals↗
PubMed1995

Interaction of the effects of domperidone and sub-anaesthetic concentrations of isoflurane on the immediate and sustained hypoxic ventilatory response in humans.

Twenty normal male subjects with brisk hypoxic ventilatory responses were recruited and ventilatory responses to sustained isocapnic hypoxia (SaO2 80.4 (SD 1.3)% for 20 min) were studied on separate days under four conditions: hypoxia alone, with or without domperidone, and 0.1 MAC of end-tidal isoflurane, with or without domperidone. Ventilatory variables were subjected to analysis of variance with estimation of the effects of isoflurane and domperidone, and their interaction. Isoflurane reduced the initial increase in ventilation significantly by 3.12 (95% confidence limits 1.69, 4.55) litre min-1 (P < 0.05) and domperidone increased the initial increase in ventilation by 1.78 (0.35, 3.21) litre min-1 (P < 0.05). Neither isoflurane nor domperidone affected the subsequent ventilatory decline. No interaction was found between these agents. These results confirm that 0.1 MAC of isoflurane suppressed the initial hypoxic ventilatory response but not the subsequent ventilatory decline when hypoxia was sustained. Domperidone offset the suppressive effect of isoflurane on the hypoxic ventilatory response but no interaction was detected.

Adult↗
PubMed1995

Audit of sickness absence and fitness-for-work referrals.

Since referrals in relation to sickness absence and fitness to continue work constitute an important part of occupational physicians' workloads, a study was carried out to audit this activity. Randomly selected referrals (u = 162) were audited by external peer review in relation to the information provided in the referral request, the consultation records and responses of the occupational physicians, and the response times linking the referral, the consultation and the response. The study showed that the referral record was adequate when specifying or quantifying long-term absences (90% and 84% of relevant cases, respectively) but questions or information regarding other relevant issues were much less frequent, eg only 12% of the referral records provided a description of the job or task. The physicians' response rate was high in relation to likely date of return to work (96%) but lower for other relevant items. In all the issues audited, the frequency of the physicians' responses was higher than the frequency with which the relevant questions were posed to them, thus suggesting 'added value' in the formulation of the problem by the physicians. The response times (often interpreted as a measure of health care quality) did not correlate usefully with the completeness of the responses as determined by peer review audit. Occupational physicians should aspire to achieve a validated standard of assessment and communication which can be audited.

Absenteeism↗
PubMed1995

A direct midseptal approach to slow atrioventricular nodal pathway ablation.

OBJECTIVES: The purpose of this study was to describe a midseptal approach to selective slow pathway ablation for the treatment of AV nodal reentrant tachycardia (AVNRT). In addition, predictors of success and recurrence were evaluated. METHODS: Selective ablation of the slow AV nodal pathway utilizing radiofrequency (RF) energy and a midseptal approach was attempted in 60 consecutive patients with inducible AVNRT. RESULTS: Successful slow pathway ablation or modification was achieved in 59 of 60 patients (98%) during a single procedure. One patient developed inadvertent complete AV block (1.6%). A mean of 2.7 +/- 1.4 RF applications were required with mean total procedure, ablation, and fluoroscopic times of 191 +/- 6.3, 22.8 +/- 2.3, and 28.2 +/- 1.8 minutes, respectively. The PR and AH intervals, as well as the antegrade and retrograde AV node block cycle length, were unchanged. However, the fast pathway effective refractory period was significantly shortened following ablation (354 +/- 13 msec vs 298 +/- 12 msec; P = 0.008). The A/V ratio at successful ablation sites were no different than those at unsuccessful sites (0.22 +/- 0.04 vs 0.23 +/- 0.03). Junctional tachycardia was observed during all successful and 60 of 122 (49%) unsuccessful RF applications (P < or = 0.0001). A residual AV nodal reentrant echo was present in 15 of 59 (25%) patients. During a mean follow-up of 20.1 +/- 0.6 months (11.5-28 months) there were four recurrences (5%), 4 of 15 (27%) in patients with and none of 44 patients without residual slow pathway conduction (P = 0.002). CONCLUSIONS: A direct midseptal approach to selective ablation of the slow pathway is a safe, efficacious, and efficient technique. Junctional tachycardia during RF energy application was a highly sensitive but not specific predictor of success and residual slow pathway conduction was associated with a high rate of recurrence.

Adolescent↗
PubMed1995

Asbestos contamination in paraffin tissue blocks.

Electron microscopic analyses of tissue samples embedded in paraffin are routinely performed as a means of validating (establishing) the asbestos exposure of persons diagnosed with mesothelioma, a rare form of cancer often identified as being caused by exposure to asbestos. During analysis of tissue samples claimed to contain asbestos, we observed asbestos contamination in the paraffin of the tissue block. To investigate the extent to which such contamination is prevalent in tissue block samples, we obtained and analyzed samples of paraffin blocks from hospitals in six major cities and found them to contain measurable concentrations of asbestos. Whether this asbestos contamination originated in the virgin wax or was a result of processing has not been established. This result, which has not been previously reported, raises significant concerns about the validity of analyses for asbestos in tissue embedded in paraffin. In particular, diagnoses in which the presence of asbestos in tissue samples is taken as being indicative of past asbestos exposure, especially for those cases in which no known exposure has occurred, and studies purporting to show migration of asbestos to other organs in the body following inhalation or ingestion of asbestos require critical reevaluation. The need for reevaluation is particularly acute if appropriate control blanks were not evaluated as part of the studies.

Asbestos↗
PubMed1994

Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease. Coumadin Aspirin Reinfarction (CARS) Pilot Study Group.

The hypothesis that the combination of low-dose aspirin and warfarin therapy is more effective than aspirin alone in secondary prophylaxis after myocardial infarction is to be examined in the Coumadin Aspirin Reinfarction Study. This pilot study addressed the safety and anticoagulation effect of a fixed, low-dose combination in 114 patients (aged 64 +/- 8 years, 85% men) with stable coronary artery disease receiving 3 mg of warfarin plus 80 mg of aspirin daily for 8 weeks. The international normalized ratio (INR) was measured within 72 hours of initial therapy, and weekly. Of the 110 patients with evaluable INRs, 87 patients (79%) maintained the 3 + 80 mg combination, 19 (17%) had the dose reduced to 1 mg warfarin + 80 mg aspirin, and 4 (4%) discontinued therapy because of a confirmed INR of > or = 4.5. At steady state, patients had INRs of 1.48 +/- 0.41 (3 + 80 mg group) and 1.21 +/- 0.23 (1 + 80 mg group), and inter- and intra-patient variability (estimated by the mean of the between- and within-patient SDs at steady state) was 0.49 +/- 0.08 and 0.13 +/- 0.14, respectively. There was no apparent effect of age on INR distribution. Microscopic hematuria was the most frequent (20%) adverse clinical event, but was unrelated to the INR. Three patients required discontinuation of therapy because of bleeding events (persistent hematuria and epistaxis). A fixed low-dose combination of warfarin and aspirin results in a predictable and stable increase in the INR in a large proportion of patients with coronary artery disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Clinical and electrophysiologic features and role of catheter ablation techniques in adult patients with automatic atrioventricular junctional tachycardia.

A total of 8 patients with junctional tachycardia (JT) were included for study. Patients with JT had a supraventricular arrhythmia that was initiated by a junctional complex without PR prolongation and episodes of atrioventricular (AV) dissociation. JT could not be initiated by pacing and occurred either spontaneously (3 patients) or with isoproterenol (5 patients). Tachycardia could be consistently terminated by either carotid sinus massage (1 patient), intravenous adenosine (2 patients), or critically timed ventricular premature complexes (3 patients). In 6 of the 8 other patients, tachycardia foci (atrial or ventricular) or mechanisms (AV node reentry) were found. Two patients underwent complete AV junctional ablation and 2 had termination of tachycardia without change in the AV conduction by perinodal application of radiofrequency lesions. AVJT appears to be due to abnormal automaticity and may be successfully ablated by application of radiofrequency energy to perinodal areas.

Adult↗
PubMed1994

Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis.

Folic acid was covalently conjugated to 66-nm liposomes via spacers of various lengths in an attempt to target the liposomes to KB cells expressing folate receptors. Spacers of short and intermediate lengths were unable to mediate association of folate-conjugated liposomes with receptor-bearing cells, however, use of a 250 A polyethyleneglycol spacer (PEG, M(r) approximately 3350) permitted avid uptake of the liposomes at approximately 2.5 x 10(5) sites/cell. The binding of folate-PEG liposomes to KB cells could be competitively inhibited by excess free folate or by antiserum against the folate receptor, demonstrating the interaction is mediated by the cell surface folate-binding protein. Following binding, cell-associated folate-PEG liposomes were internalized by folate-receptor-mediated endocytosis at 37 degrees C but not at 4 degrees C. These folate-PEG liposomes show potential for delivering large quantities of low molecular weight compounds nondestructively into folate receptor-bearing cells.

Biological Transport↗
PubMed1994

Surgically staged patients with prostatic carcinoma treated with definitive radiotherapy: fifteen-year results.

OBJECTIVE: To assess the long-term outcome of patients with lymphadenectomy-staged prostate cancer treated with external beam radiotherapy. METHODS: A retrospective analysis was performed on all patients with prostate cancer who underwent staging pelvic lymphadenectomy before treatment with definitive radiotherapy from 1970 to February 1978. This included 71 patients who were evaluated for a minimum of fifteen years. No patients were lost to follow-up. Thirty-five patients were node negative and 36 were node positive. RESULTS: Fifteen-year actuarial overall survival, cause-specific survival, and local control for the 20 patients with clinically organ-confined disease (T1b-T2 N0M0) was 40 percent, 75 percent, and 92 percent, respectively. The results for the 15 T3 N0M0 patients were 15 percent, 22 percent, and 60 percent. Patients with positive nodes did much worse, with rates of 5 percent, 6 percent, and 45 percent. Thirty-four patients received hormonal therapy at the time of first failure. No patient who was clinically free of disease at fifteen years had an elevated level of prostate-specific antigen (PSA). CONCLUSIONS: Our data suggest excellent results in a cohort of patients (T1b-T2 N0M0) treated with primary radiotherapy who would be considered candidates for radical prostatectomy. Outcome is significantly worse in patients with T3 lesions and node-positive disease.

Actuarial Analysis↗
PubMed1994

Radiofrequency catheter ablation as a cure for idiopathic tachycardia of both left and right ventricular origin.

OBJECTIVES: The purpose of this study was 1) to investigate the efficacy and safety of radiofrequency energy catheter ablation as curative treatment for idiopathic tachycardia of both left and right ventricular origin, and 2) to compare the usefulness of different methods used to map the site of origin of idiopathic ventricular tachycardia. BACKGROUND: Percutaneous radiofrequency catheter ablation has been used with dramatic success in the treatment of patients with Wolff-Parkinson-White syndrome, atrioventricular node reentrant tachycardia and bundle branch reentrant tachycardia. Limited data are available on the use of radiofrequency energy catheter ablation as curative treatment for idiopathic tachycardia of both left and right ventricular origin. METHODS: Twenty-eight consecutive patients (13 to 71 years old) presenting with idiopathic ventricular tachycardia were enrolled in the study. The site of origin of both left and right ventricular tachycardia was mapped using earliest endocardial activation times during tachycardia and by pace mapping. These mapping techniques were compared. RESULTS: Radiofrequency ablation was successful in all eight patients (100%) with left ventricular tachycardia. Tachycardia recurred in one patient. The ablation procedure was complicated by mild aortic insufficiency in one patient. Right ventricular outflow tract tachycardia was successfully ablated in 17 (85%) of 20 patients. The success rate at follow-up was 85%. In one patient, the ablation procedure was complicated by acute ventricular perforation and death. Pace maps from successful ablation sites were better than pace maps from unsuccessful sites (p < 0.004). Endocardial activation times at successful ablation sites were not different from unsuccessful sites (p < 0.13). CONCLUSIONS: Radiofrequency catheter ablation is an effective treatment for idiopathic ventricular tachycardia. The site of origin of tachycardia is best identified using pace mapping. Significant complications can occur and should be considered in the risk/benefit analysis for each patient.

Adolescent↗
PubMed1994

Radiofrequency catheter ablation in the treatment of supraventricular tachycardia in the elderly.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of radiofrequency catheter ablation for the treatment of supraventricular tachycardias in an elderly (> or = 70 years of age) group of patients. BACKGROUND: Supraventricular tachycardias are the most common form of cardiac arrhythmia and affect all age groups. Although usually well tolerated in youth, supraventricular tachycardias may be associated with disabling symptoms and have life-threatening potential in the elderly. In addition, antiarrhythmic agents are less well tolerated and may be associated with a higher incidence of toxicity in the elderly. METHODS: From May 1989 to March 1993, 454 patients underwent a radiofrequency catheter ablation procedure at the University of California, San Francisco, for the treatment of symptomatic supraventricular tachycardia. Sixty-seven of these patients were > or = 70 years of age and constituted the study group. Patients underwent one of the following catheter ablation procedures: complete atrioventricular (AV) junctional ablation for ventricular rate control in patients with atrial fibrillation (37 patients), AV node modification for the treatment of AV node reentrant tachycardia (17 patients), accessory pathway ablation (9 patients), ablation of the "slow zone" to cure atrial flutter (4 patients) and atrial tachycardia ablation (1 patient). One patient underwent ablation for both AV node reentrant tachycardia and atrial flutter. RESULTS: Success was achieved in 67 (98.5%) of 68 ablation procedures. There were no procedural or early deaths. The overall complication rate was 7.4%, and only one patient (1.5%) had long-term sequelae (permanent cardiac pacing for complete heart block). At a mean (+/- SD) follow-up of 22.1 +/- 12.9 months, 63 (94%) of 67 patients were alive, with no antiarrhythmic agents for the treatment of their presenting arrhythmia. CONCLUSIONS: In this series radiofrequency catheter ablation appears to be an effective and safe treatment option for elderly patients (> or = 70 years of age) with a variety of symptomatic, drug-resistant supraventricular tachycardias. Because of the high incidence of severe symptoms associated with tachycardic episodes, the expense and the possible severe proarrhythmic problems associated with antiarrhythmic medications in this age group, catheter ablation may be considered an early rather than a "last resort" treatment option.

Aged↗