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Biomedical subjects

B P Lee

Publications and source records attributed to B P Lee.

At least 19 recordsLinked to original sources
PubMed2002

Human placental trophoblast as an in vitro model for tumor progression.

The human placenta is a highly invasive tumor-like structure in which a subpopulation of placental trophoblast cells known as the "extravillous trophoblast" (EVT) invades the uterine decidua and its vasculature to establish adequate fetal-maternal exchange of molecules. By utilizing in vitro-propagated short-lived EVT cell lines we found that molecular mechanisms responsible for their invasiveness are identical to those of cancer cells; however, unlike cancer cells, their proliferation, migration, and invasiveness in situ are stringently controlled by decidua-derived transforming growth factor (TGF)-beta. By SV40T antigen transfection of normal EVT cells followed by a forced crisis regimen in culture we produced an immortalized premalignant derivative that is hyperproliferative, hyperinvasive, and deficient in gap-junctional intercellular communication. Both premalignant and malignant EVT (JAR and JEG-3 choriocarcinoma) cell lines were found to be TGF-beta-resistant. Using these cell lines, we investigated genetic changes responsible for transition of the normal EVT cells to premalignant and malignant phenotype. Hyperinvasiveness in both cases resulted from a downregulation of tissue inhibitor of metalloprotease (TIMP)-1 and plasminogen activator inhibitor (PAI)-1 genes. In contrast to normal EVT cells, both cell types failed to upregulate these genes in response to TGF-beta. Loss of TGF-beta response in malignant EVT cells was explained by the loss of expression of Smad3 gene. Differential mRNA display of normal and premalignant EVT cells identified up- and down-regulation of numerous known or novel genes in premalignant EVT cells, with potential oncogenic and (or) tumor-suppressor functions, e.g., loss of fibronectin and insulin-like growth factor binding protein (IGFBP-5). Premalignant EVT cells also lost IGF receptor type 2 (IGFR-II). IGFBP-5 was shown to be a negative regulator of IGF-1-induced proliferation of premalignant EVT cells, so that loss of IGFBP-5 as well as IGFR-II permitted their unrestricted proliferation in an IGF-I-rich microenvironment of the fetal-maternal interface. The present model may be a good prototype for identifying genetic changes underlying epithelial tumor progression.

Cell Line↗
PubMed2001

Differential gene expression in premalignant human trophoblast: role of IGFBP-5.

Tumorigenesis results from genetic alterations that occur in a stepwise manner giving rise to cells with increasingly cancer-like characteristics. We used in vitro propagated first trimester human extravillous trophoblast (EVT) cells to identify genetic changes responsible for the transition of the EVT from a normal to premalignant stage. The model used consisted of a normal invasive EVT (HTR8) cell line and its premalignant derivative (RSVT2/C) generated by transfection with the SV40 Tag and selected using a forced crisis regimen. RSVT2/C display increased proliferative, migratory and invasive behavior, unresponsiveness to anti-proliferative and anti-invasive signals of TGFbeta and a deficiency in gap junctional intercellular communication. These cells, however, were unable to form colonies on soft agar or tumors in nude mice and are thus defined as premalignant. Differential display revealed 18 gene sequences, 7 with unknown and 11 with known identity, showing altered expression between the normal HTR8 and premalignant RSVT2/C cell lines. The known sequences include the potential tumor suppressors insulin-like growth factor binding protein (IGFBP)-5 and fibronectin (FN) and potential protooncogenes such as chromokinesin (KIF4), alternative splicing factor (SF2), dynein, DNA polymerase epsilon (DNApol epsilon) and NF-kappaB activating kinase (NAK). The role of the remaining 4 genes upregulated in the premalignant EVT is presently unknown and these are FK506 binding protein (FKBP) 25, histone protein (HP1Hs)-gamma, nucleoporin (Nup) 155 and an 82 kDa acidic human protein. The functional role of IGFBP-5 was examined in the control of proliferation, migration and invasiveness of RSVT2/C cells measured in vitro. IGFBP-5 alone had no effect on these properties of RSVT2/C cells. Furthermore, unlike normal EVT cells, RSVT2/C cells exhibited refractoriness to the migration stimulating signals of IGF-II, which was explained by the loss or downregulation of the IGF type 2 receptor (IGF-R2). RSVT2/C cells, however, expressed the IGF type 1 receptor (IGF-R1) and responded to IGF-I by increased proliferation. This response was blocked with increasing concentrations of IGFBP-5. These results suggest that the loss of IGFBP-5 and possibly IGF-R2, both of which can sequester IGF-I from IGF-R1, permits unhindered proliferation of the premalignant EVT in an IGF-I rich environment of the fetal-maternal interface. The functions of the other differentially expressed genes, some of which are essential for cell cycle progression or cell survival require further investigation.

Base Sequence↗
PubMed2001

Total knee arthroplasty in diabetic patients: a study of 109 consecutive cases.

The outcome of 109 consecutive total knee arthroplasties in 86 diabetic patients was studied. There were 73 women and 13 men, with a mean age of 69 years (range, 56-84 years). All the patients were followed for at least 36 months. The mean follow-up period was 42 months (range, 36-60 months). In the early postoperative period (< or =1 month), the overall wound infection rate was 7.3% (8 knees). The risk of deep joint infection was 5.5% (6 knees). Of the patients, 15% (17 knees) developed a urinary tract infection after the operation. The superficial and deep infection rates were higher when compared with a similar study in the general population. Maximum precautions should be taken for diabetic patients undergoing total knee arthroplasties.

Aged↗
PubMed2000

Different roles of two subgroups of lung vagal C-fiber afferents in the tachypneic response to pulmonary air embolism in dogs.

It is known that lung vagal C-fiber afferents play an important role in eliciting the tachypneic response to pulmonary air embolism (PAE), and can be subgrouped as those with low resistance (LRC) and those with high resistance (HRC) to perivagal capsaicin. In this study, we investigated the relative contributions of vagal LRC and HRC C-fiber afferents to the PAE-induced tachypneic response. Phrenic activity was recorded from 10 anesthetized, paralyzed, and artificially ventilated dogs. PAE was induced by infusion of air into the vein (2 ml/min, 1 ml/kg). During control conditions, induction of PAE produced a shortening in expiratory duration with no significant change in inspiratory duration, resulting in tachypnea. The PAE-induced tachypneic response was totally abolished by perivagal capsaicin treatment with a method (capsaicin concentration, 6 mg/ml; treatment duration, 25-30 min) that blocks the conduction of LRC C-fiber afferents, but not that of HRC C-fiber afferents. This tachypneic response was not affected by cooling of both vagi to a temperature (4.5 degrees C) that blocks the conduction of HRC C-fiber afferents, but not that of LRC C-fiber afferents. A bilateral cervical vagotomy virtually eliminated this tachypneic response. These results suggest that LRC C-fiber afferents are responsible for eliciting the reflex tachypneic response to PAE, whereas HRC C-fiber afferents play no vital role.

Anesthesia↗
PubMed2000

Antigen-specific cancer immunotherapy using a GM-CSF secreting allogeneic tumor cell-based vaccine.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cell-based vaccines are currently one of the major forms of cancer vaccines. However, the preparation of GM-CSF-transduced autologous tumor vaccines is time-consuming and technically challenging. In addition, the host antigen presenting cells, rather than the tumor vaccine cells themselves, present tumor-specific antigens and prime the host T cells. Therefore, we tested the efficacy of antigen-specific allogeneic tumor vaccines. We used human papillomavirus 16 (HPV-16) E7 protein as a model tumor antigen, which is associated with the development of most cervical carcinoma. B16, a C57BL/6 (H-2(b)) derived melanoma cell line, was genetically engineered to produce GM-CSF alone (B16GM), HPV-16 E7 alone (B16E7), or both (B16GME7). These vaccine cells were injected into BALB/c (H-2(d)) mice (10(6) cells/mouse). Two weeks later, mice were challenged with 10(5) live HPV-16 E7(+) BL-1 (H-2(d)) tumor cells and monitored for tumor progression twice weekly. To determine the effective cell population in the antitumor immunity elicited by B16GME7, we carried out in vivo antibody depletion experiments using CD4 and CD8 specific antibodies. In addition, as a measure of the immune responses produced by B16GME7, we performed an in vitro cytotoxic T lymphocyte assay using a standard chromium release method. We found that all of the mice vaccinated with B16GME7 remained tumor free 49 days post-BL-1 challenge. In contrast, mice vaccinated with B16GM and B16E7 did not show any tumor protection against a similar dose of BL-1 cells. Furthermore, the antitumor immunity produced by B16GME7 was dependent on both CD4 and CD8 T cells. In addition, E7-specific cytotoxic T lymphocyte activity could be readily demonstrated in mice immunized with B16GME7. These results suggest that allogeneic tumor cells transduced with GM-CSF and the tumor antigen, HPV-16 E7, cannot only generate an E7-specific cytotoxic T lymphocytes response in vitro, but can also elicit a potent antitumor immune response against an E7 expressing tumor in vivo.

Animals↗
PubMed2000

Elevated expression of hepatic proliferative markers during early hepatocarcinogenesis in hepatitis-B virus transgenic mice lacking mdr1a-encoded P-glycoprotein.

Recent studies have shown that expression levels of the multidrug resistance gene MDR1, which encodes the drug transporter P-glycoprotein, correlate with prognostic outcomes of certain tumor types. These findings suggest that expression of MDR1 may affect tumor behaviors. To address this issue further, we investigated the expression of mdr1a, a human MDR1 homolog, on the development of hepatocellular carcinoma in a transgenic mouse model carrying the liver-targeted expression of human hepatitis-B virus (HBV) surface antigen. The pathogenetic program was compared in HBV mice carrying either mdr1a(+/+) or mdr1a(-/-). We found that the expressions of proliferative activity markers, Ki67 nuclear antigen, and proliferating cell nuclear antigen were elevated in mdr1a(-/-) mice younger than 10 wk in comparison with those in the same age group of wild-type animals. Replication in the hepatic population as determined by bromodeoxyuridine incorporation tended to support observation that mdr1a(-/-) mice exhibited elevated labeling indices in this age group. Moreover, histologic staining and flow-cytometric analysis showed that the mdr1a(-/-) animals exhibited a higher cell population with polyploidy than did the mdr1a(+/+) counterparts of the same age. However, no significant differences in the expression of the liver-injury markers serum alanine transaminase and aspartate transaminase were observed. Although our results showed that absence of mdr1a expression is correlated with modest enhanced proliferative characteristics in the livers at stage before the development of hepatocellular carcinoma, the overall life spans between these two strains of mice were not significantly different. The implication of these findings to the role of P-glycoprotein in tumor development and cancer chemotherapy is discussed.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Use of low molecular weight heparin for prevention of deep vein thrombosis in total knee arthroplasty--a study of its efficacy in an Asian population.

INTRODUCTION: The aims of this paper were to study the incidence of deep vein thrombosis following total knee replacement in an Asian population and to evaluate the role of low molecular weight heparin for deep vein thrombosis in this setting. MATERIALS AND METHODS: We prospectively studied two groups of 100 consecutive patients undergoing total knee replacement separately. Group 1 did not receive any low molecular weight heparin and group 2 received low molecular weight heparin, nodraparin calcium (Fraxiparine) according to body weight. The sex distribution, age group, weight, preoperative knee and function scores, and postoperative rehabilitation were similar for both groups. A single ultrasound technician performed ultrasound duplex scan of both lower limbs on the seventh postoperative day. RESULTS: The incidence of deep vein thrombosis in group 1 was 14% (14 patients, 5 proximal vein thromboses and 9 distal vein thromboses) while in group 2, no patients developed deep vein thrombosis. There was no increased incidence, either local or systemic, of major bleeding complications with the use of low molecular weight heparin. CONCLUSION: While the incidence of deep vein thrombosis following total knee replacement in an Asian population appears lower compared to Western populations, the use of low molecular weight heparin for thromboprophylaxis appears to further reduce the incidence without major bleeding complications.

Activities of Daily Living↗
PubMed1999

Two subgroups of lung vagal C-fibers with different vulnerabilities to blockades by perivagal capsaicin and vagal cooling in dogs.

Perivagal capsaicin treatment and vagal cooling are two techniques that have been widely used to study the respiratory reflexes mediated by lung vagal C-fibers because they can block the neural conduction of unmyelinated fibers. We hypothesized that there are two subgroups of lung vagal C-fibers which have different vulnerabilities to blockades by these two techniques. To test this hypothesis, afferent activity arising from lung vagal C-fibers was recorded in 29 anesthetized, paralyzed, and artificially ventilated dogs. Afferent C-fiber activity was recorded before and after various concentrations of perivagal capsaicin treatment or before and during various temperatures of vagal cooling. Of the 89 lung vagal C-fibers studied, 73 fibers were classified as the group of "low resistance" to capsaicin, while the other 16 were classified as the group of "high resistance". The former group differed from the latter due to their afferent activity being blocked at relatively low concentrations of perivagal capsaicin and at relatively low temperatures of vagal cooling. Our results suggest that lung vagal C-fibers can be categorized into two subgroups, based upon their different blocking thresholds for perivagal capsaicin and vagal cooling. Our data may provide information for researchers to further differentiate the respiratory reflexes originating from these two subgroups of lung vagal C-fibers.

Animals↗
PubMed1999

Filler-induced composition waves in phase-separating polymer blends.

The influence of immobile filler particles (spheres, fibers, platelets) on polymer-blend phase separation is investigated computationally using a generalization of the Cahn-Hilliard-Cook (CHC) model. Simulation shows that the selective affinity of one of the polymers for the filler surface leads to the development of concentration waves about the filler particles at an early stage of phase separation in near critical composition blends. These "target" patterns are overtaken in late-stage phase separation by a growing "background" spinodal pattern characteristic of blends without filler particles. The linearized CHC model is used to estimate the number of composition oscillations emanating from isolated filler particles. In far-off-critical composition blends, an "encapsulation layer" grows at the surface of the filler rather than a target pattern. The results of these simulations compare favorably with experiments on filled phase-separating ultrathin blend films in which the filler particles are immobilized on a solid substrate.

Journal Article↗
PubMed1998

Acute effects of thyroid hormones on the production of adrenal cAMP and corticosterone in male rats.

The acute effects of thyroid hormones on glucocorticoid secretion were studied. Venous blood samples were collected from male rats after they received intravenous 3,5,3'-triiodothyronine (T3) or thyroxine (T4). Zona fasciculata-reticularis (ZFR) cells were treated with adrenocorticotropic hormone (ACTH), T3, T4, ACTH plus T3, or ACTH plus T4 at 37 degrees C for 2 h. Corticosterone concentrations in plasma and cell media, and also adenosine 3',5'-cyclic monophosphate (cAMP) production in ZFR cells in the presence of 3-isobutyl-1-methylxanthine, were determined. The effects of thyroid hormones on the activities of steroidogenic enzymes of ZFR cells were measured by the amounts of intermediate steroidal products separated by thin-layer chromatography. Administration of T3 and T4 suppressed the basal and the ACTH-stimulated levels of plasma corticosterone. In ZFR cells, both thyroid hormones inhibited ACTH-stimulated corticosterone secretion, but the basal corticosterone was inhibited only with T3 > 10(-10) M or T4 > 10(-8) M. Likewise, T3 or T4 at 10(-7) M inhibited the basal- and ACTH-stimulated levels of intracellular cAMP. Physiological doses of T3 and T4 decreased the activities of 3 beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11 beta-hydroxylase. These results suggest that thyroid hormones counteract ACTH in adrenal steroidogenesis through their inhibition of cAMP production in ZFR cells.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Total hip arthroplasty for the treatment of an acute fracture of the femoral neck: long-term results.

We reviewed the long-term results of 126 consecutive total hip arthroplasties performed with cement in eighteen men and 108 women who had an acute fracture of the femoral neck. The patients had a mean age of seventy-five years (range, thirty-nine to eighty-nine years) at the time of the operation and were followed for a minimum of 10.1 years (or until the patient died or had a revision operation) and a maximum of 20.4 years. The median duration of follow-up was 8.8 years for all patients and 15.7 years for the twenty-two patients who were alive at the end of the study period. Six hips (5 per cent) were revised because of aseptic loosening. Survivorship analysis revealed that the probability of survival of the prosthesis without revision (with 95 per cent confidence intervals) was 95 per cent (91 to 99 per cent) at five years, 94 per cent (88 to 98 per cent) at ten years, 89 per cent (79 to 97 per cent) at fifteen years, and 84 per cent (66 to 97 per cent) at twenty years. Of the 118 patients who were alive at the one-year postoperative examination, 117 (99 per cent) had no pain or mild pain and eighty-one (69 per cent) had regained or had an improvement in the preoperative level of function. At the latest follow-up examination, eighty-seven (86 per cent) of the 102 patients who were available still had no pain or only mild pain. Twenty-six patients (21 per cent) had had perioperative medical complications, and twenty-one patients (17 per cent) had had operative complications, including thirteen patients (10 per cent) who had had a dislocation of the hip. Total hip arthroplasty performed in elderly patients for the treatment of an acute fracture of the femoral neck was associated with a higher rate of complications than usually is reported for hemiarthroplasty in such patients. However, the total hip arthroplasty provided good clinical results and was associated with long-term survival of the prosthesis.

Adult↗
PubMed1998

Isolated metal-backed patellar component revision following total knee arthroplasty.

BACKGROUND: Twenty-two consecutive revisions for failed metal-backed patellar components following total knee arthroplasty in 17 patients were retrospectively reviewed. All had similar total condylar knee prosthesis inserted with retention of the posterior cruciate ligament and resurfacing of the patella with a metal-backed component. There were 3 male and 14 female patients. RESULTS: The mean time to failure of the patellar component was 60 months (range 26 to 93 months). The majority of patients presented with metallic crepitus (86.4%) and knee pain (72.7%). At surgery, full thickness polyethylene wear exposing the metal-backing was present in 81.8% with surface damage of the femoral components present in 40.9%. All 22 cases underwent successful isolated patellar component revision with all polyethylene patellar components. CONCLUSION: Resurfacing of the patella in total knee arthroplasty with metal-backed patellar components carries a significant risk of early failure and the use of these components is no longer practised at our institution.

Aged↗
PubMed1997

Mechanisms underlying stimulation of rapidly adapting receptors during pulmonary air embolism in dogs.

We investigated the mechanisms underlying stimulation of rapidly adapting receptors (RARs) during pulmonary air embolism (PAE). Impulses were recorded from RARs in 43 anesthetized, open-chest and artificially ventilated dogs. Forty one out of 56 RARs were stimulated by infusion of air into the right atrium (0.2 ml/kg per min for 10 min). As a group (n = 56), RAR activity increased from a baseline of 1.2 +/- 0.2 to a peak of 4.3 +/- 0.3 impulses/breath at 8-10 min after the onset of PAE induction. PAE also caused an increase in total lung resistance and a decrease in dynamic lung compliance. Studies were repeated in 33 RARs initially stimulated by PAE. In nine receptors, hyperinflation of the lungs performed at the termination of the second PAE induction largely reversed both the afferent and bronchomotor responses. Furthermore, the residual PAE-evoked activity subsequent to hyperinflation was almost eliminated by elevation in the heart position. In another 24 receptors, the responses of RARs to PAE were unaltered by pretreatment with saline (n = 8) or dimethylthiourea (a hydroxyl radical scavenger; n = 8), but was significantly attenuated by pretreatment with ibuprofen (a cyclooxygenase inhibitor: n = 8). These results suggest that: (1) the increased RAR activity following PAE is associated primarily with an increase in bronchomotor tone and secondarily with the mechanical action of the beating heart impacting on lung tissues; and (2) cyclooxygenase products may be involved in this sensory stimulation.

Afferent Pathways↗
PubMed1997

Bone-graft augmentation for acetabular deficiencies in total hip arthroplasty. Results of long-term follow-up evaluation.

The results of 102 consecutive primary and revision total hip arthroplasties performed with bone-grafting for acetabular bone deficiencies were reviewed at an average of 10.2 years (range, 4-18.6) after surgery. Ninety-one percent had structural bone defects and 57% had underlying developmental dysplasia of the hip. Overall acetabular revision rates for aseptic loosening were 8% at 5 years and 26% at 10 years. In addition, in the patients with developmental dysplasia who had primary hip arthroplasties, acetabular revision rates for aseptic loosening were 3 and 18% at 5 and 10 years, respectively. Ninety-six percent of all uninfected grafts incorporated. Bulk grafts fared better than particulate grafts. No difference in failure rate was noted between primary and revision hip arthroplasty, type of deficiency, or amount of graft coverage. Although early results are encouraging, acetabular failure increased significantly with longer follow-up evaluation; however, graft incorporation was successful and facilitated subsequent revision surgery.

Acetabulum↗
PubMed1997

Mechanisms of stimulation of vagal pulmonary C fibers by pulmonary air embolism in dogs.

We investigated the involvement of the cyclooxygenase metabolites and hydroxyl radical (.OH) in the stimulation of vagal pulmonary C fibers (PCs) by pulmonary air embolism (PAE). Impulses were recorded from PCs in 51 anesthetized, open-chest, and artificially ventilated dogs. Fifty of 59 PCs were stimulated by infusion of air into the right atrium (0.2 ml.kg-1.min-1 for 10 min). As a group (n = 59), PC activity increased from a baseline of 0.4 +/- 0.1 to a peak of 1.7 +/- 0.2 impulses/s during the period from 1 min before to 2 min after the termination of PAE induction. In PCs initially stimulated by PAE induction, PAE was repeated after the intervening treatment (iv) with saline (n = 9), ibuprofen (a cyclooxygenase inhibitor; n = 11), or dimethylthiourea (a .OH scavenger; n = 12). The responses of PCs to PAE were not altered by saline vehicle but were abolished by ibuprofen and significantly attenuated by dimethylthiourea. Although hyperinflation of the lungs reversed the PAE-induced bronchomotor responses, it did not reverse the stimulation of PCs (n = 8). These results suggest that 1) cyclooxygenase products are necessary for the stimulation of PCs by PAE, whereas changes in lung mechanics are not, and 2) the functional importance of cyclooxygenase products may be mediated in part through the formation of .OH.

Animals↗
PubMed1997

Arthroscopic synovectomy of the elbow for rheumatoid arthritis. A prospective study.

The short-term assessment of 14 arthroscopic synovectomies of the elbow in 11 patients with rheumatoid arthritis showed that 93% achieved a short-term rating of excellent or good on the Mayo Elbow Performance Score. At the most recent assessment at an average of 42 months, however, only 57% maintained excellent or good results; four had required total elbow replacement. Although rehabilitation is facilitated by an arthroscopic procedure the results deteriorate more rapidly than after open synovectomy. This may be due to the limitations of the arthroscopic technique and is consistent with experience of the similar procedure in the knee. Recognition of the short-term gain and the potential for serious nerve injury should be considered when offering arthroscopic synovectomy.

Arthritis, Rheumatoid↗
PubMed1997

Inhibition of corticosterone secretion by thyroxine in male rats.

The effects of thyroxine (T4) on the secretion of corticosterone both in vivo and in vitro in male rats were studied. Rats were thyroidectomized (Tx) or sham Tx. The Tx rats were subcutaneously with T4 (20 micrograms/kg) or saline once daily for two weeks. In an in vitro experiment, adrenal glands were incubated with ACTH, T4, or ACTH plus T4 in the presence or absence of 0.5 mM 3-isobutyl-1-methylxanthine (IBMX) at 37 degrees C for 60 min. Medium and ether-extracted plasma samples were analyzed for corticosterone by radioimmunoassay (RIA). The accumulation of cyclic adenosine monophosphate (cAMP) in adrenal tissues after incubation with IBMX was measured by RIA. The levels of plasma corticosterone in Tx rats were significantly increased as compared with euthyroid rats. T4 replacement in Tx rats restored plasma corticosterone to euthyroid level. Administration of T4 in vitro resulted in an inhibition of both basal and ACTH-stimulated release of corticosterone. Both basal and ACTH-stimulated generations of cAMP in adrenal tissues were decreased by T4. These results suggest that T4 inhibits the spontaneous and ACTH-stimulated secretion of corticosterone by acting directly at adrenal glands via a decrease in cAMP production.

Adrenal Glands↗