Questions about palivizumab (Synagis)
Explore the source record for details and available documents.
Antibodies, Monoclonal↗
Biomedical subjects
S L Lee
Publications and source records attributed to S L Lee.
Superoxide scavenging effect of Ginkgo biloba extract on serotonin-induced mitogenesis.
We have reported previously that serotonin (5-HT) stimulates the mitogenesis of bovine pulmonary artery smooth muscle cells (SMCs) through active transport of 5-HT and cellular signaling that includes elevation of superoxide (O2.-) and enhancement of protein tyrosine phosphorylation. Ginkgo biloba extract 501 (EGb 501), which has been demonstrated to act as an antioxidant, was found to block both the elevated O2.- and the proliferative and hypertrophic influences of 5-HT on SMCs, but not to directly inhibit the associated activation of NAD(P)H oxidase or the stimulation of phosphorylation of GTPase-activating protein (GAP). A similar effect of Ginkgo biloba extract 501 occurred on Chinese hamster lung fibroblasts (CCL-39), where 5-HT receptor, as opposed to transporter, action has been associated with mitogenesis. We conclude from these studies that Ginkgo biloba extract 501 quenches O2.- formation by 5-HT, thereby blocking its mitogenic effect. Stimulation of protein tyrosine phosphorylation of GAP by 5-HT appears to precede the elevation of O2.-.
Animals↗
Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia.
Local hypoxemia and stasis trigger thrombosis. We have demonstrated previously that in a murine model of normobaric hypoxia pulmonary fibrin deposition is a result of expression of tissue factor, especially in oxygen-deprived mononuclear phagocytes (MPs). We now show that transcription factor early-growth-response gene product (Egr-1) is rapidly activated in hypoxia, both in vitro and in vivo, and is responsible for transcription and expression of tissue factor in hypoxic lung. MPs and HeLa cells subjected to hypoxia (pO2 approximately 13 torr) had increased levels of tissue factor transcripts (approximately 18-fold) and an increased rate of transcription (approximately 15-fold), based on nuclear run-on analysis. Gel-shift analysis of nuclear extracts from hypoxic MPs and HeLa cells demonstrated increased DNA-binding activity at the serum response region (SRR; -111/+14 bp) of the tissue factor promoter at Egr-1 motifs. Using 32P-labeled Egr consensus oligonucleotide, we observed induction of DNA-binding activity in nuclear extracts from hypoxic lung and HeLa cells because of activation of Egr-1, by means of supershift analysis. Transient transfection of HeLa cells with chimeric plasmids containing wild-type or mutant SRR from the tissue factor promoter showed that intact Sp1 sites are necessary for basal promoter activity, whereas the integrity of Egr-1 sites was required for hypoxia-enhanced expression. A central role for Egr-1 in hypoxia-mediated tissue factor expression was confirmed by experiments with homozygous Egr-1 null mice; wild-type mice subjected to oxygen deprivation expressed tissue factor and showed fibrin deposition, but hypoxic homozygous Egr-1 null mice displayed neither tissue factor nor fibrin. These data delineate a novel biology for hypoxia-induced fibrin deposition, in which oxygen deprivation-induced activation of Egr-1, resulting in expression of tissue factor, has an unexpected and central role.
Animals↗
Thy-1, a novel marker for angiogenesis upregulated by inflammatory cytokines.
We identified the cell surface glycoprotein Thy-1 on the endothelium of newly formed blood vessels in four models of angiogenesis in adult rats. Anti-Thy-1 staining showed that Thy-1 was upregulated in adventitial blood vessels after balloon injury to the carotid artery. Preabsorption with a rat Thy-1-Ig fusion construct eliminated all immunoreactivity and thus confirmed the specificity of the Thy-1 staining. Thy-1 was also expressed in the endothelium of small blood vessels formed after tumor implantation in the cornea, in periureteral vessels formed after ligation of the renal artery, and in small blood vessels of the uterus formed during pregnancy. In contrast with its expression during adult angiogenesis, Thy-1 was not expressed in the endothelium of blood vessels during embryonic angiogenesis. In vitro, the inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha upregulated Thy-1 mRNA by 8- and 14-fold, respectively. Vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-beta, and platelet-derived growth factor-BB had no effect on Thy-1 mRNA. Thus, Thy-1 appears to be a marker of adult but not embryonic angiogenesis. The upregulation of Thy-1 by cytokines but not growth factors indicates the importance of inflammation in the pathogenesis of adult angiogenesis.
Angioplasty, Balloon↗
Superoxide as an intermediate signal for serotonin-induced mitogenesis.
Serotonin (5-HT) stimulates tyrosine phosphorylation and proliferation of bovine pulmonary artery smooth muscle cells (SMC) through its active transport (Lee et al, 1991). The present studies show that 5-HT also rapidly elevates O2.- formation by these cells within 10 minutes as measured by a lucigenin-enhanced chemiluminescence assay. The O2.- free radical quencher, Tiron, and N-acetyl-cysteine, a substrate for glutathione, block both the 5-HT-induced formation of O2.- and cellular proliferation. Similarly, inhibition of 5-HT transport with imipramine or treatment of cells with diphenyliodonium, a NAD(P)H oxidase inhibitor, block both 5-HT-induced elevation of O2.- and cellular proliferation. Alpha-hydroxyfarnesylphosphonic acid, an inhibitor of p21ras, also blocks 5-HT-induced proliferation. Endothelial cells from the same vessel show neither 5-HT-induced proliferation nor stimulation of O2.- formation. We conclude that 5-HT induced cellular proliferation of SMC through signaling pathways that utilize its transport system and O2.- formation.
Animals↗
Molecular cloning of a novel potassium-dependent sodium-calcium exchanger from rat brain.
We have isolated a novel cDNA clone from rat cerebral cortex encoding a protein of 670 amino acids (NCKX2) that has significant similarity to the 1199-amino acid-long Na/Ca-K exchanger of bovine rod outer segment (NCKX1). NCKX2 transcripts are 10.5 kilobase pairs in length and are expressed abundantly in neurons throughout the brain and with much lower abundance in selected other tissues. The predicted topology of the rat NCKX2 protein is very similar to that of bovine NCKX1, beginning with a solitary transmembrane segment (M0), which is removed as a "signal peptide" in bovine NCKX1, an extracellular loop, a cluster of five transmembrane spanning segments (M1 to M5), a long cytoplasmic loop, and a final hydrophobic cluster (M6 to M11). Within the hydrophobic clusters, rat NCKX2 shares 80% identity and 91% similarity with bovine NCKX1. The two larger hydrophilic loops are much shorter in NCKX2 than in NCKX1, accounting largely for the difference in length between the two proteins, and are dissimilar in sequence except for a 32-amino acid stretch with 69% identity in the cytosolic loop. NCKX2 was epitope-tagged in the extracellular domain and was shown to be expressed at the surface of transfected HEK cells. Analysis of NCKX2 function by fluorescent imaging of fura-2-loaded transfected cells demonstrated that NCKX2 is a potassium-dependent sodium/calcium exchanger.
Amino Acid Sequence↗
Utility of biochemical markers of bone turnover in the follow-up of patients treated with bisphosphonates.
Biochemical markers of bone turnover are often measured in patients treated with antiresorptive agents to monitor the effects of therapy. In order for a change in these markers to clearly indicate treatment effect, the change in the markers must exceed the amount of spontaneous variation typically seen with no treatment. Based on the measured long-term variability of markers in untreated patients, we defined a minimum significant change (MSC), that is, a change that was sufficiently large that it was unlikely to be due to spontaneous variability. We also examined the changes in markers of bone turnover in subjects treated with pamidronate to see how often observed changes in turnover after treatment exceeded the MSC. We found that urinary markers of bone resorption are best measured on 2-hour fasting samples, because results on random urine showed poor precision and less decline with therapy. We also found that of all the markers, urinary N-telopeptide cross-links (NTX) had the greatest decline after therapy (58%), although it also had the highest long-term variability (29.5%). The marker that most often showed a decline with treatment that exceeded the MSC was serum bone-specific alkaline phosphatase where 74% of observed changes exceeded the MSC. Other markers that often showed a decline with treatment that exceeded the MSC were 2-hour fasting urine NTX and free deoxypyridinoline, where 57% and 48%, respectively, of changes in therapy exceeded the MSC. The ideal marker would combine the large decline after treatment characteristic of NTX (60-70%) with the good precision of bone-specific alkaline phosphatase.
Alkaline Phosphatase↗
Toxic nodular goiter. Toxic adenoma and toxic multinodular goiter.
Solitary toxic adenoma and toxic multinodular goiter are very common forms of thyrotoxicosis around the world. Advances in molecular biology and genetics have led to new insights into the pathogenesis of these disorders. Current theories on autonomy in the thyroid are discussed in this article. The therapeutic roles of surgery, radioiodine ablation, and percutaneous ethanol administration also are reviewed.
Adenoma↗
Epidemiology of bovine ephemeral fever virus infection in Taiwan.
Sick animals with excessive nasal discharges and protruding tongue as a result of dyspnea were observed in the August of 1996. Eight strains of BEF virus were isolated from heparinized blood samples of the affected cattle. Most of the affected cattle were difficult to be treated and had a poor prognosis. A total of 516 farms in the 9 districts of Taiwan were affected in 1996. Among a population of 110,247 dairy cattle, 14,993 (13.6%) cattle were found to be clinically ill. During the epidemic, 1,685 (11.3%) affected cattle were culled or dead after the onset of the disease. Furthermore, a strain of Ibaraki virus was isolated from the blood sample of a sick cattle that showed pyrexia, labored respiration and solitary behavior in the affected farm. The cattle with Ibaraki virus infection had typical symptoms of BEF at the early stage of the disease, but neither stomatitis nor pharyngoesophageal paralysis was observed at the onset of the disease. The outbreak was presumably brought about by the low level or non-immune status of a large cattle population due to the negligence of BEF vaccination. Therefore, the disease easily recurred in Taiwan after a typhoon episode in the August of 1996, which resulted in the proliferation of biting midges in the field. No difference in the antigenicty was found between the new and the previous isolates of BEF virus. As analyzed by cross neutralization test, the isolated BEF viruses showed no relationship to the Kimberley and Berrimah viruses that were isolated from the blood of cattle and related to BEF virus in Australia. We have tried to advise farmers that they must vaccinate their cattle annually to prevent BEF outbreak in the future.
Animals↗
Alternative promoters and cardiac muscle cell-specific expression of the Na+/Ca2+ exchanger gene.
Many studies have investigated the regulation of the Na+/ Ca2+ exchanger, NCX1, but limited data exist on transcriptional regulation of the NCX1 gene. We have identified the transcription start sites of three tissue-specific alternative promoters of NCX1 transcripts from rat heart, kidney, and brain. We have characterized the cardiac NCX1 promoter, from which the most abundant quantities of NCX1 transcripts are expressed. Transfection of primary cardiac myocytes, CHO cells, and COS-7 cells with overlapping genomic DNA fragments spanning the NCX1 cardiac transcription start site has uncovered a cardiac cell-specific minimum promoter from -137 to +85. The cardiac NCX1 promoter is TATA-less but has putative binding sites for cardiac-specific GATA factors, an E box, and an Inr as well as multiple active enhancers. The kidney NCX1 promoter has a typical TATA box and binding sites for several tissue-specific factors. The brain NCX1 promoter is very GC-rich and possesses several Sp-1 binding sites consistent with its ubiquitous expression.
Alternative Splicing↗
Characterization of the circadian system of NGFI-A and NGFI-A/NGFI-B deficient mice.
The genes NGFI-A (also known as EGR-1, zif/268, and Krox-24) and NGFI-B (nur/77) have previously been shown to be induced in the SCN of rats and hamsters by photic stimulation during the subjective night. The purpose of this study is to determine whether these genes are also induced in the SCN of mice and, if so, to characterize the circadian system of animals in which either NGFI-A or both NGFI-A and NGFI-B were eliminated by homologous recombination. In wildtype mice, NGFI-A mRNA was found to be induced in the SCN as in other rodent species. Therefore, wheel-running activity was recorded from null mutants and wildtype controls under LD 12:12 and DD conditions. Mice of all three strains appeared to entrain normally to LD 12:12 and could re-entrain to both phase advances and phase delays of the light cycle. The response of the circadian pacemaker of all three genotypes to acute light pulses appeared to be normal. The retinal innervation of the SCN in NGFI-A-/- mice and the photic induction of Fos in the SCN of both NGFI-A-/- and NGFI-A-/-/B-/- mice were indistinguishable from wildtype mice. These results indicate that induction of NGFI-A and NGFI-B is not required for photic entrainment or phase shifting of the mouse circadian system.
Adaptation, Physiological↗
Randomized trial of pamidronate in patients with thyroid cancer: bone density is not reduced by suppressive doses of thyroxine, but is increased by cyclic intravenous pamidronate.
Patients taking suppressive doses of T4 are thought to have accelerated bone loss and increased risk of osteoporosis. We therefore randomize 55 patients taking suppressive doses of T4 to treatment with pamidronate (APD) 30 mg i.v. every 3 months for 2 yr (APD/T4), or placebo (placebo/T4). Patients had measurements of bone mineral density (BMD) of the spine, hip, radius, and total body every 6 months for 2 yr. There was no significant bone loss at any site in the placebo/T4 group. Ninety five percent confidence intervals excluded a rate of bone loss > 0.89%/yr for the spine and > 0.31%/yr at the total hip. When men were excluded from the analysis, there still was no significant bone loss for the placebo/T4 group, and confidence intervals did not change. The APD/T4 group showed increases in spine (4.3%, P = 0.0001), total hip (1.4%, P < 0.05), and trochanteric (3.0%, P = 0.0001) BMDs. In conclusion, premenopausal women and men on suppressive therapy with T4 do not lose bone rapidly, and are not at increased risk of developing osteoporosis. A regimen of 30 mg APD given every 3 months for 2 yr causes significant suppression of bone resorption and increases in BMD, and may be an acceptable alternative treatment for osteoporosis in patients who cannot tolerate oral bisphosphonates.
Adult↗
Post-therapy iodine-131 localization in unsuspected large renal cyst: possible mechanisms.
Sensitive and specific, whole-body 131I scintigraphy remains an important technique for diagnosing metastases from differentiated papillary or follicular thyroid carcinoma. False-positive 131I localization is well recognized and can occur in a variety of conditions. We present a case of intense 131I localization in a previously unsuspected large renal cyst; the lesion was not visualized on routine preablation diagnostic 131I scintigraphy but was obvious on post-therapeutic whole-body imaging, underscoring the value of post-therapy imaging in detecting abnormalities not apparent on diagnostic studies. Radioiodine within the urinary bladder or, at times, the renal collecting system is expected, because 131I excretion is primarily by glomerular filtration. In the case presented here, 131I activity within the renal cyst supports the concept that iodide is subject to an active secretory process by the renal tubule.
Carcinoma, Papillary↗
New inhibitors of thrombin and other trypsin-like proteases: hydrogen bonding of an aromatic cyano group with a backbone amide of the P1 binding site replaces binding of a basic side chain.
Highly effective thrombin inhibitors have been obtained by preparing boronic acid analogues of m-cyano-substituted phenylalanine and its incorporation into peptides. The cyano group enhances binding by several orders of magnitude. For example, Ac-(D)Phe-Pro-boroPheOH binds to thrombin with a Ki of 320 nM and the Ki of Ac-(D)Phe-Pro-boroPhe(m-CN)-OH is 0.79 nM. Protein crystal structure determination of trypsin complexed to H-(D)Phe-Pro-boroPhe(m-CN)-OH indicates that the aromatic side chain is bound in the P1 binding site and that the cyano group can act as a H-bond acceptor for the amide proton of Gly219. Enhanced binding for inhibitors containing the m-cyano group was observed for coagulation factor Xa and for the factor VIIa.tissue factor complex [Ki values of Ac-(D)Phe-Pro-boroPhe(mCN)-OH are 760 and 3.3 nM, respectively]. This result is consistent with the sequence homology of these two enzymes in the P1 binding site. Two enzymes lacking the strict homology in the P1 binding site, pancreatic kallikrein and chymotrypsin, did not exhibit significantly enhanced binding.
Amides↗
A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis.
BACKGROUND/PURPOSE: The authors evaluated prospectively the utility of ultrasonography, Tc-99m-DISIDA hepatobiliary scintigraphy, and liver needle biopsy in differentiating biliary atresia (BA) from intrahepatic cholestasis in 73 consecutive infants who had cholestasis. METHODS: Sixty three ultrasonographic examinations of 61 infants with 7.0-MHz transducer were carried out, focusing on the fibrous tissue at the porta hepatis. The authors defined the triangular cord (TC) as visualization of a triangular or tubular shaped echogenic density just cranial to the portal vein bifurcation on a transverse or longitudinal scan. RESULTS: Although 17 of 20 ultrasonographic examinations from infants who had BA denoted TC, 43 ultrasonographic examinations from infants with either neonatal hepatitis (NH) or other causes of cholestasis denoted no TC, showing a diagnostic accuracy of 95% with 85% sensitivity and 100% specificity. Investigation with Tc-99m-DISIDA hepatobiliary scintigraphy showed that 24 of 25 infants who had BA had no gut excretion, and 16 of 46 infants who had either NH or other causes of cholestasis had gut excretion, showing a diagnostic accuracy of 56% with 96% sensitivity and 35% specificity. Therefore, gut excretion of tracer excluded BA, but no gut excretion of tracer needed further investigations as liver needle biopsy. Forty-four liver needle biopsies were carried out in 19 infants who had BA and 24 infants who had either NH or other causes of cholestasis. Although 18 of 20 biopsy findings in infants who had BA were correctly interpreted as having BA, 23 of 24 biopsy results in infants who had either NH or other causes of cholestasis were correctly diagnosed, showing a diagnostic accuracy of 93% with 90% sensitivity and 96% specificity. CONCLUSIONS: Since the introduction of ultrasonographic TC sign in the diagnosis of BA by our institution, we have found that it seemed to be a simple, time-saving, highly reliable, and non-invasive tool in the diagnosis of BA from other causes of cholestasis. The authors propose a new diagnostic strategy in the evaluation of infantile cholestasis with emphasis on ultrasonographic TC sign as first priority of investigations. When the TC is visualized, prompt exploratory laparotomy is mandatory without further investigations. When the TC is not visualized, hepatobiliary scintigraphy is the next step. Excretion of tracer into the small bowel actually rules out BA. Liver needle biopsy is reserved only for the infants with no excretion of tracer. The authors believe that a correct decision regarding the need for surgery can be made in almost all cases with infantile cholestasis by this multidisciplinary approach.
Algorithms↗
Association of Tyr phosphorylation of GTPase-activating protein with mitogenic action of serotonin.
We have previously shown that serotonin (5-HT) induces both hyperplasia and hypertrophy of pulmonary artery smooth muscle cells (SMC) but not of endothelial cells (EC) through its high-affinity uptake. The present studies demonstrate rapid enhancement by 5-HT of Tyr phosphorylation of proteins, including p120, which also occurs in SMC but not in EC. The p120 protein was identified as GTPase-activating protein (GAP) by immunoprecipitation. Its phosphorylation occurred within minutes and preceded other events associated with 5-HT-induced mitogenesis. Tyr kinase (TK) and 5-HT uptake inhibitors and 8-bromoadenosine 3',5'-cyclic monophosphate blocked both the 5-HT-induced DNA synthesis and Tyr phosphorylation of GAP. Vanadate elevated DNA synthesis and Tyr phosphorylation of GAP of both control and 5-HT-treated cells. 5-HT failed to alter Tyr phosphorylation of GAP in cellular homogenates, as opposed to intact cells. In the presence of 3-isobutyl-1-methylxanthine, 5-HT inhibited cellular growth, presumably through its action on 5-HT1A or 5-HT4 receptors and elevation of adenosine 3',5'-cyclic monophosphate, but this was not associated with an alteration of Tyr phosphorylation of GAP. Similarly, a 5-HT1 or 5-HT2 receptor agonist failed to stimulate Tyr phosphorylation or DNA synthesis of SMC. Stimulation of cellular proliferation and enlargement produced by 1 microM 5-HT were totally abolished by TK inhibitors that did not affect 5-HT uptake. These data indicate that Tyr phosphorylation of GAP may act as an intermediate signal in 5-HT-induced mitogenesis of SMC which requires cellular internalization of 5-HT rather than its action on a membrane receptor.
1-Methyl-3-isobutylxanthine↗
A new role for an old molecule: serotonin as a mitogen.
Serotonin (5-hydroxytryptamine) has been known for the last half century to influence vasoactivity and to participate in neurotransmission. More recently, this compound has been recognized to cause proliferation of a variety of cells in culture, including those of vascular smooth muscle. Furthermore, the proliferative effect is synergistic with that of more conventional growth-producing polypeptides. A hypertrophic, as well as a proliferative response, has been shown to occur in some smooth muscle cells. Whether the mitogenic effect is initiated through a cell surface receptor or a serotonin transporter, or both depending on the cell type, is currently unresolved. Most evidence indicates that cellular cyclic nucleotides play an important role in the intracellular signaling process for growth regulation by serotonin, and newer studies point to protein phosphorylation pathways as being important in the mitogenic response. It has been proposed that, through these signaling pathways, serotonin plays an important role in remodeling of both the pulmonary and systemic circulations.
Animals↗
Inhibitory effect of heparin on serotonin-induced hyperplasia and hypertrophy of smooth muscle cells.
Serotonin (5-HT) produces both hyperplastic and hypertrophic effects on smooth muscle cell (SMC) in culture. Heparin is known to inhibit serum-induced hyperplasia of SMC but has not been previously tested on the stimulatory effect of 5-HT on SMC. Our present data show that at 24 h heparin inhibited by 50% the stimulation of 3H-thymidine incorporation into bovine pulmonary artery SMC and at 7 days totally reversed both cellular proliferation and enlargement of SMC produced by 1 microM 5-HT. Heparin failed to alter 5-HT uptake by SMC, but inhibited the stimulation of tyrosine phosphorylation of GTPase-activating protein, a proposed intermediate in the 5-HT stimulatory process. Thus heparin inhibits both hyperplastic and hypertrophic effects of 5-HT on SMC, perhaps through the inhibition of a phosphorylated intermediate protein.
Animals↗