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Biomedical subjects

P Sun

Publications and source records attributed to P Sun.

At least 19 recordsLinked to original sources
PubMed1999

Identification of a novel zinc finger gene, zf5-3, as a potential mediator of neuroblastoma differentiation.

We established a unique parental neuroblastoma cell line, NUB-7, which mimics the bipotentiality of neuroblastoma in vivo along neuronal and Schwann cell lineages following dibutyryl cAMP and retinoic acid treatments, respectively. Differential display identified a putative novel zinc finger gene as a potential differentiation-responsive gene coincident with retinoic acid treatment of NUB-7. This cDNA clone, now designated zf5-3, was mapped to chromosome 19 using somatic cell hybrids, and a larger cDNA clone further localized this gene to band 13.1-13.2 by fluorescent in situ hybridization. zf5-3 possesses 4 characteristic zinc finger DNA-binding motifs as determined by its nucleic acid and proposed amino acid sequence. Expression of zf5-3 is restricted to fetal neuronal, hepatic and renal tissues and their tumor-derived cell lines, including 8/9 neuroblastomas and 2/2 malignant rhabdoid tumors of kidney. The restricted expression in the kidney of zf5-3 to collecting tubules and ureter epithelium is suggestive of an ectodermal histogenesis of malignant rhabdoid tumors of kidney. During development of the fetal human brain, high levels of zf5-3 mRNA are restricted to the mitotically active, undifferentiated neuroblasts. Morphological evidence of overt differentiation was generally accompanied by a marked loss in zf5-3 expression. Therefore, the neuronal tissue expression profile and the down-regulation coincident with retinoic acid-induced neuroblastoma maturation implicate zf5-3 as a potential mediator of their differentiation.

Amino Acid Sequence↗
PubMed1999

Tissue plasminogen activator does not increase neuronal damage in rat models of global and focal ischemia.

BACKGROUND: Intravenous tissue plasminogen activator (tPA) is the only approved treatment for acute ischemic stroke. Recent results from both in vitro and in vivo animal model experiments suggest the possibility that tPA is neurotoxic. METHODS: The authors evaluated the putative neurotoxicity of tPA in both global and focal animal models of ischemic stroke. Global ischemia was induced in male Wistar rats using a modified four-vessel occlusion technique, with percentage neuronal injury assessed at 7 days through necrotic and normal cell count in the CA1 region. Transient focal ischemia was induced in male spontaneously hypertensive rats subjected to middle cerebral artery clipping, with measurement of cortical infarct volume at 24 hours. tPA was administered in 1, 5, or 10 mg/kg doses given intravenously as a 10% bolus, 90% over the following hour, analogous to current human treatment protocols. RESULTS: In the global model, percent hippocampal injury was 60%+/-23%, 66%+/-26%, 55%+/-26%, and 52%+/-12% in the saline control, 1, 5, and 10 mg/kg tPA groups, respectively. In the focal model, after 120 minutes of ischemia, the control infarct size was 151+/-39 mm3, and for the group given 10 mg/kg of tPA, it was 158+/-28 mm3. CONCLUSIONS: Despite sublethal insults, with moderate injury induced by ischemia, there was no evidence that increasing doses of tPA exacerbated ischemic injury.

Animals↗
PubMed1999

Cyanide interaction with redox modulatory sites enhances NMDA receptor responses.

Activation of NMDA receptors plays an important role in cyanide neurotoxicity. Cyanide indirectly activates the receptor by inducing neuronal release of glutamate and also enhances receptor-mediated responses by a direct interaction with the receptor complex. This study investigated the mechanism in cerebellar granule cells by which cyanide enhances NMDA-induced Ca2+ influx. Cyanide (50 microM) increased the influx of Ca2+ over the NMDA concentration range of 0.5-500 microM. Experiments showed that cyanide does not interact with the receptor's glycine or PKC mediated phosphorylation regulatory sites. N-ethylmaleimide, a thiol alkylating agent which inactivates the redox regulatory sites of the receptor, blocked the enhancing effect of cyanide. Pretreatment of cells with 5,5-dithio-bis-2-nitrobenzoic acid (DTNB), a compound that oxidizes the receptor redox sites, had no effect on the response to cyanide. On the other hand, the nonpermeant reducing agents, dithiothreitol or cysteine, further increased the cyanide effect. These observations can be explained by cyanide interacting with redox sensitive disulfide groups that are not accessible to the non-permeant reducing agents. It is proposed that cyanide interacts with a redox site(s) located either on the intracellular receptor domain or in the transmembrane hydrophobic domain. Furthermore the enhancement by cyanide of the excitotoxic actions of NMDA involves receptor sites that are sensitive to oxidation/reduction and this interaction contributes to the neurotoxic action of cyanide.

Animals↗
PubMed1999

Crystallization and preliminary X-ray diffraction studies of the lipopolysaccharide core biosynthetic enzyme ADP-L-glycero-D-mannoheptose 6-epimerase from Escherichia coli K-12.

ADP-L-glycero-D-mannoheptose 6-epimerase is a 240 kDa NAD-dependent nucleotide diphosphosugar epimerase from Escherichia coli K12 which catalyzes the interconversion of ADP-D-glycero-D-mannoheptose and ADP-L-glycero-D-mannoheptose. ADP-L-glycero-D-mannoheptose is a required intermediate for lipopolysaccharide inner-core and outer-membrane biosynthesis in several genera of pathogenic and non-pathogenic Gram-negative bacteria. ADP-L-glycero-D-mannoheptose 6-epimerase was overexpressed in E. coli and purified to apparent homogeneity by chromatographic methods. Three crystal forms of the epimerase were obtained by a hanging-drop vapor-diffusion method. A native data set for crystal form III was collected in-house on a Rigaku R-AXIS-IIC image plate at 3.0 A resolution. The form III crystals belong to the monoclinic space group P21. The unit-cell parameters are a = 98.94, b = 110.53, c = 180.68 A and beta = 90.94 degrees. Our recent results show that these crystals diffract to 2.0 A resolution at the Cornell High Energy Synchrotron Source. The crystal probably contains six 40 kDa monomers per asymmetric unit, with a corresponding volume per protein mass (Vm) of 4.11 A3 Da-1 and a solvent fraction of 70%.

Carbohydrate Epimerases↗
PubMed1998

p53-independent role of MDM2 in TGF-beta1 resistance.

Transforming growth factor-beta (TGF-beta) inhibits cell proliferation, and acquisition of TGF-beta resistance has been linked to tumorigenesis. A genetic screen was performed to identify complementary DNAs that abrogated TGF-beta sensitivity in mink lung epithelial cells. Ectopic expression of murine double minute 2 rescued TGF-beta-induced growth arrest in a p53-independent manner by interference with retinoblastoma susceptibility gene product (Rb)/E2F function. In human breast tumor cells, increased MDM2 expression levels correlated with TGF-beta resistance. Thus, MDM2 may confer TGF-beta resistance in a subset of tumors and may promote tumorigenesis by interference with two independent tumor suppressors, p53 and Rb.

Animals↗
PubMed1998

Automated intima-media thickness: the Los Angeles Atherosclerosis Study.

Common carotid artery (CCA) intima-media thickness (IMT) from B-mode ultrasound is a widely used measure of early atherosclerosis. This study evaluated within- and between-sonographer reproducibility of automated edge-tracking IMT using a low-cost mobile scanner. B-mode images of the left and right CCA were acquired on two occasions (interval of 2-14 days) by two sonographers for 38 subjects, aged 31-75 y. Reproduciblity error was measured as the mean absolute difference (MAD+/-SEM) and the standard deviation of differences (SDdelta) between repeated measurements. Within-sonographer (MAD=0.027+/-0.006 mm; SDdelta=0.044 mm) and between-sonographer errors (MAD=0.041+/-0.008 mm; SDdelta=0.064) in IMT (mean=0.74, SD=0.14) of a single artery were small compared to those of other protocols. Combined averaging across both body positions and arteries reduced intersonographer MAD by 47% (MAD=0.022+/-0.003 mm; SDdelta=0.029 mm). These data demonstrate that the proposed IMT protocol reduces reproducibility error by more than 50% relative to several protocols used in other major studies.

Adult↗
PubMed1998

Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine.

The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.

Adolescent↗
PubMed1998

Dietary calcium, calcium supplementation, and blood pressure in African American adolescents.

BACKGROUND: Intake of calcium from the diet is inversely associated with blood pressure in observational studies and animal models but randomized trials in humans have found only small effects of calcium supplementation on blood pressure. A blood pressure-lowering effect of calcium supplementation may thus be restricted to persons with a low intake of calcium from the diet and specific genetic or other characteristics. OBJECTIVE: A randomized trial was conducted to assess the effect of calcium supplementation on blood pressure in African American adolescents. Rapid growth during adolescence may increase calcium requirements, and avoidance of milk and milk products by some African Americans can result in low intake of calcium. DESIGN: One hundred sixteen adolescents (65 girls, 51 boys; mean age: 15.8 y) were given calcium (1.5 g/d) or placebo for 8 wk in a randomized, double-blind, crossover design. Blood pressure was measured after 2, 4, and 8 wk. Dietary calcium was determined with a validated food-frequency questionnaire. RESULTS: The net effect (+/-SE) of calcium supplementation on diastolic blood pressure was a reduction of 1.9 +/- 1.1 mm Hg (P = 0.04, one-tailed t test). Blood pressure reduction was greater in adolescents with lower intake of calcium from the diet (P = 0.003, one-tailed t test for interaction): -4.9 +/- 1.6, -2.3 +/- 1.6, and 1.4 +/- 1.8 mm Hg for change in the lower (0.024-0.067 g Ca/MJ), middle (0.069-0.091 g Ca/MJ), and upper (0.093-0.217 g Ca/MJ) tertiles, respectively. No main effect on systolic blood pressure was detected. CONCLUSION: These findings suggest that calcium supplementation may lower diastolic blood pressure in African American adolescents with low dietary intakes of calcium.

Adolescent↗
PubMed1998

[Chiari malformations and hydrosyringomyelia].

INTRODUCTION: The association of hindbrain herniation, better known as Chiari malformation, and cystic cavitation of the spinal cord or hydrosyringomyelia has been well described in the literature although there is little consensus regarding its etiology, pathophysiology or optimal treatment. DEVELOPMENT: Despite a well-accepted and utilized classification system of both Chiari malformation and hydrosyringomyelia, there remains considerable disagreement regarding the proper management of these patients. CONCLUSIONS: This article reviews several popular theories on the etiology and pathophysiology of this disorder, briefly discusses the clinical features and radiologic findings associated with Chiari malformation and hydrosyringomyelia, and reviews basic surgical techniques for decompression of the cranial-cervical junction and treatment of the hydrosyringomyelia.

Arnold-Chiari Malformation↗
PubMed1998

Evaluation of buffering capacity and acid neutralizing-pH time profile of antacids.

The antacid properties of seven antacids listed in the hospital formulary of a medical center were evaluated with in vitro tests. These included not only the preliminary antacid test and acid-neutralizing capacity test as described in the United States Pharmacopeia (USP XXIII), but also a buffering pH profile test. The preliminary antacid test measured the final pH of a 10-mL solution of 0.5 N HCl 10 minutes after addition of the minimum recommended dose of an antacid, while the neutralizing capacity test measured the amount (mEq) of HCl neutralized by the minimum recommended dose in 15 minutes. The buffering pH profile recorded the pH time course of dynamic simulated gastric fluid neutralization by a dose of an antacid. In the preliminary antacid test, magnesium oxide showed the highest pH (9.52 +/- 0.14, mean +/- standard deviation, n = 3); aluminum phosphate gel yielded a final pH of 2.51 +/- 0.01, thus failing to meet the criteria of an antacid (pH > 3.5). In the acid-neutralizing capacity test, hydrotalcite had the highest neutralizing capacity (28.26 +/- 0.3 mEq), while sodium bicarbonate had the lowest (7.40 +/- 0.12 mEq). In the buffering pH profile test, aluminum-magnesium hydroxide suspensions and hydrotalcite tablets maintained a steady optimum pH (3-5) for around 1.5 hours. One tablet of calcium carbonate, sodium bicarbonate or magnesium oxide could not raise the gastric pH to above 3, but two tablets increased the pH excessively (5.3 to 8.6). The higher dose (two tablets) of aluminum hydroxide hexitol complex could not raise the pH to the optimal level. These findings demonstrate that there is disparity in the antacid effectiveness estimated by the neutralizing capacity test and the buffering pH profile test and suggest that the efficacy of an antacid cannot be accurately predicted from its acid-neutralizing capacity. The dose of antacids greatly influences the neutralizing pH profiles. Aluminum-magnesium compounds appear to provide steadier buffering than carbonate compounds or magnesium oxide.

Aluminum Compounds↗
PubMed1997

Modulation of the NMDA receptor by cyanide: enhancement of receptor-mediated responses.

The effect of cyanide on the N-methyl-D-aspartate (NMDA)-stimulated increase in cytosolic free calcium ([Ca++]i) was studied by microfluorescence in fura-2-loaded cerebellar granule cells. The response to NMDA was enhanced by NaCN over a concentration range of 20 to 100 microM. These concentrations of NaCN in the absence of NMDA had no effect on basal [Ca++]i. In comparison, NaCN did not affect K+-depolarization-induced [Ca++]i elevation. The NaCN potentiation of NMDA-evoked [Ca++]i elevation was blocked by addition of Mg++ and by the NMDA receptor antagonists 2-amino-5-phosphono-valeric acid and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine maleate. Pretreatment of the cells with pregnenolone sulfate or arachidonate, known modulators of the NMDA receptor, enhanced NaCN action. The voltage-sensitive calcium channel blockers nifedepine and diltiazem did not affect the NaCN-induced potentiation. Additionally, the NaCN action was not altered when tetrodotoxin was used to block Na+ channel-mediated glutamate release. In patch-clamp studies, NaCN increased the amplitude and duration of NMDA-stimulated whole-cell currents. NaCN also enhanced the NMDA receptor response in single-channel patch-clamp experiments. In the outside-out patch recording configuration, NaCN increased the NMDA receptor channel opening frequency without affecting single-channel conductance or mean channel open time. These results indicate that cyanide interacts directly with the NMDA receptor channel complex to enhance receptor-mediated responses.

2-Amino-5-phosphonovalerate↗
PubMed1997

Secondary craniofacial management following initial correction of nonsyndromic craniosynostosis.

Marked technical improvements in the surgical management of craniosynostosis have come hand-in-hand with refinements in anesthesia, intensive care, and radiographic image analysis. At the beginning of the second century of the care of these patients, we now have a variety of sophisticated options that represent safer, more physiologically sound and aesthetically more pleasing options for the correction of secondary problems in craniosynostosis.

Cephalometry↗
PubMed1997

Gas chromatographic-mass spectrometric determination of benzo[a]pyrene and chrysene diol epoxide globin adducts in humans.

The efficacy of a newly developed gas chromatography-negative ion chemical ionization-mass spectrometry-selected ion monitoring (GC-NICI-MS-SIM) assay for measuring globin adducts of benzo[a]pyrene (B[a]P) and chrysene diol epoxides in human was evaluated. In this pilot study, smokers and nonsmokers were selected as exposed and nonexposed groups. Using [2H12]r-7,t-8,9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyren e ([2H12]trans,anti-B[a]P-tetraol) as an internal standard, B[a]P-tetraols released from globin after hydrolysis and derivatization were quantified by GC-NICI-MS-SIM. Levels of trans-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene (chrysene-DE)-globin adducts were estimated by assuming that the recovery and the MS response of the perdeuterated B[a]P-tetraol internal standard reflected the recovery and MS response of chrysene tetraols. The assay was found to be reproducible and sensitive enough to detect both analytes in all samples. The mean levels of B[a]P-tetraols released from the corresponding benzo[a]pyrene diol epoxide (BPDE) globin adducts in smokers were significantly higher than those in nonsmokers, i.e., 2.6 +/- 0.6 SE fmol/mg globin (ranging from 1.2 to 7.8 fmol/mg globin) in smokers and 0.97 +/- 0.05 SE fmol/mg globin (ranging from 0.7 to 1.3 fmol/mg globin) in nonsmokers (P < 0.01). Interestingly, estimated levels of chrysene-DE-globin adducts in the same subjects were about two orders of magnitude higher than those of the globin adducts of BPDE. The mean of the chrysene-DE adducts in smokers was estimated to be 310 +/- 30 SE fmol/mg globin (ranging from 190 to 460 fmol/mg globin) and that in nonsmokers was 250 +/- 25 SE fmol/mg globin (ranging from 110 to 380 fmol/mg). Although the estimated mean of chrysene-DE adducts with globin in smokers appeared to be about 25% higher than in nonsmokers, the difference was not significant (P = 0.06). The results of this study demonstrate the feasibility of the GC-NICI-MS-SIM method for measurement of BPDE globin adducts in humans.

Benzopyrenes↗
PubMed1996

Association of serum total cholesterol with coronary disease and all-cause mortality: multivariate correction for bias due to measurement error.

Measurement error in the exposure under investigation is an important but often ignored source of bias in observational studies. The authors examined the impact of measurement error in the association between total serum cholesterol and 16-year coronary heart disease and all-cause mortality in a cohort of 6,137 middle-aged men of Japanese descent in the Honolulu Heart Program (1973-1988). A Cox regression model that enables modeling of survival time with correction for measurement errors in multiple covariates was employed. After controlling for age, body mass index, systolic blood pressure, smoking status, alcohol consumption, dietary cholesterol, and total calorie intake, a difference of one standard deviation (38 mg/dL) in total cholesterol was associated with a significant increase in the risk of coronary disease death (uncorrected hazard ratio = 1.35). After correction for measurement errors in total cholesterol and covariates (except smoking and age), the estimated hazard ratio increased to 1.65 (a 22% increase). A U-shaped relation was observed between total cholesterol levels and the risk of all-cause mortality. This association was then examined with a quadratic model and with a two-slope or V-shaped regression model. In the quadratic fit, the magnitude of the quadratic total cholesterol term increased threefold after the adjustment for measurement error. In the V fit, the hazard ratio of all-cause death corresponding to a change in one standard deviation above 214 mg/dL (the nadir of the V) was 1.15, and increased to 1.49 (by 29%) after the correction. The corresponding hazard ratio of a change in one standard deviation below 214 mg/dL was 1.11, and increased to 1.37 (by 23%) after the correction. The authors conclude that the impact of elevated total cholesterol on the risk of coronary disease and all-cause mortality may be greater than previously estimated with standard methods of analysis. In addition, the correction for measurement error in total cholesterol and covariates did not explain the excess mortality associated with low total cholesterol. More research is needed to elucidate the fundamental issues underlying the U-shaped association, i.e., confounding versus causal implications.

Aged↗
PubMed1996

Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV.

The ability of activating transcription factor-1 (ATF1) or the cAMP response element-binding protein (CREB) to enhance transcription can be stimulated by increases in intracellular Ca2+ concentrations. To identify protein kinases which may mediate the ability of Ca2+ to activate these transcription factors, we compared the ability of constitutively active forms of several Ca2+/calmodulin-dependent protein kinases (CaM kinases) to activate ATF1 or CREB. We find that constitutively active CaM kinase I and IV can activate both ATF1 and CREB. In addition, expression vectors for full-length CaM kinase I and IV were able to augment the ability of Ca2+ influx to activate ATF1 or CREB consistent with a role for these kinases in mediating transcriptional responses to Ca2+ signaling. In contrast, CaM kinase II was unable to activate either ATF1 or CREB. These findings provide a potential mechanism that may permit variation in the ability of ATF1 and CREB to respond to changes in intracellular Ca2+ concentrations depending on differences in the relative concentrations of specific CaM kinases.

Activating Transcription Factor 1↗