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R Chang

Publications and source records attributed to R Chang.

At least 73 records · Page 4Linked to original sources
PubMed1996

Small peptides as potent mimetics of the protein hormone erythropoietin.

Random phage display peptide libraries and affinity selective methods were used to isolate small peptides that bind to and activate the receptor for the cytokine erythropoietin (EPO). In a panel of in vitro biological assays, the peptides act as full agonists and they can also stimulate erythropoiesis in mice. These agonists are represented by a 14- amino acid disulfide-bonded, cyclic peptide with the minimum consensus sequence YXCXXGPXTWXCXP, where X represents positions allowing occupation by several amino acids. The amino acid sequences of these peptides are not found in the primary sequence of EPO. The signaling pathways activated by these peptides appear to be identical to those induced by the natural ligand. This discovery may form the basis for the design of small molecule mimetics of EPO.

Amino Acid Sequence↗
PubMed1996

Prediction of outcome in critically ill patients using artificial neural network synthesised by genetic algorithm.

BACKGROUND: Decisions about which patients to admit to intensive care and how long to keep them there are difficult. A flexible computer-based mathematical model which is sensitive to the complexity of intensive care medicine, and which accurately models prognosis, seems highly desirable. METHODS: We have created, optimised by genetic algorithms, trained, and evaluated the performance of an artificial neural network (ANN) in the clinical setting of systemic inflammatory response syndrome and haemodynamic shock. 258 patients were selected from an intensive care database of 4484 patients at a London teaching hospital and randomised to a network training set (168) and a test set (90). The outcome evaluated was death during that hospital admission and the performance of the neural net was compared (by receiver operating characteristic [ROC] curves and by Brier scores) with that of a logistic regression model. FINDINGS: Artificial neural network performance increased with successive generations; the best-performing ANN was created after 7 generations and predicted outcome more accurately than the logistic regression model (ROC curve area 0.863 vs 0.753). INTERPRETATION: In this study, ANNs have lent themselves particularly well to modelling a complex clinical situation; we suggest that this relates to their inherently flexible nature which accommodates interactions between the clinical input fields. In addition, we have demonstrated the value of a second computational technique (genetic algorithms) in "tuning" ANN performance. These techniques can potentially be implemented in individual intensive care units; the outcome models which they will generate will be sensitive to local practice. Analysis of such accurate clinical outcome models may empower clinicians with a hitherto unappreciated degree of insight into those elements of their clinical practice which are most relevant to their patients' outcome.

Adult↗
PubMed1996

In vivo role of the Sp1 site neighboring sterol-responsive element-1 in controlling low-density lipoprotein receptor gene expression.

The in vivo role of the crucial Sp1 site neighboring sterol-responsive element-1 (SRE-1) in controlling LDL receptor gene expression in the presence or absence of sterols was examined. For this purpose the Xenopus laevis system was utilized as there are two different genes for LDL receptors in frogs which differ in their promoter region in the Sp1-binding sequence of repeat 3 present immediately adjacent to SRE-1. DNase I footprinting of promoters of both receptors showed differences in the affinity of this Sp1 site to purified transcription factor Sp1. Transcript levels of both LDL receptors were measured in livers of frogs on normal and cholesterol-enriched diets. Basal levels and extent of repression of LDL receptor gene on sterol administration were found to be dependent on the nature of the Sp1 site of repeat 3 under in vivo conditions. We conclude that this Sp1 site acts as a constitutive positive transcriptional element that forms a part of the active transcription complex irrespective of cellular sterol levels.

Animals↗
PubMed1996

Novel form of actin-based motility transports bacteria on the surfaces of infected cells.

Enteropathogenic Escherichia coli (EPEC) attach to cells (attachment) lining the intestine and induce a decrease in the number of the cells' microvilli (effacement). This attachment and effacement is followed by diarrhea, which may be explained, at least in part, to the loss of microvilli and the decreased ability of the infected cells to absorb fluids. EPEC also attach to the surfaces of a number of cultured cells including CaCo-2, LLC-PK, and PtK2 cells. The extracellular, attached EPEC induce filaments of actin to form in the cytoplasm just underneath the EPEC surface attachment sites. Beneath some of the attached EPEC, the actin filaments become organized into membrane encased columns that extend up to 6 micrometers above the cell surface creating "pedestals" on which the EPEC rest. The raised pedestals can be readily observed in stereo pairs taken using the Intermediate Voltage Electron Microscope. The concentration of non-muscle isoforms of myosin II and tropomyosin near the base of the pedestals suggests a similarity of these structures to brush border microvilli. Video microscopy indicates that these EPEC pedestals can bend and undulate, alternately growing longer and shorter while remaining tethered in place on the cell surface. Some of the attached EPEC also translocate along the cell surface, reaching speeds up to 0.07 micrometers/sec. Both types of movement are inhibited by cytochalasin D, indicating that actin polymerization in the pedestals is required for the motility of EPEC on the host cell surface. In this respect, EPEC motility on host cells resembles the intracellular motility of Listeria, but there are differences in the actin filament bundles induced by the two different bacteria. The most obvious one is the interposition of the cell membrane between EPEC and the actin filaments in the pedestal in contrast to the close apposition of actin filaments to Listeria. The intensity of fluorescence of rhodamine phalloidin is nearly uniform along most of the length of the pedestals indicating a constant number of actin filaments, whereas the fluorescence intensity decreases along the length of Listeria tails reflecting the disassembly that occurs all along the tails. Epec's movements may be a hybrid of Listeria filopodia and Aplysia inductopodia movements. This paper is the first report of a microbe attached to the extracellular surface of an infected cell propelled by an intracellular actin polymerization-dependent mechanism.

Actins↗
PubMed1996

Chiloscyllium plagiosum low-density lipoprotein receptor: evolutionary conservation of five different functional domains.

All five functional domains of the low-density lipoprotein (LDL) receptor were assembled in their modern form more than 450 million years ago, as revealed from the cloning and sequencing of an LDL receptor cDNA from Chiloscyllium plagiosum (banded cat shark). The shark LDL receptor has the same overall architecture as the mammalian and amphibian counterparts. Each of the seven cysteine-rich repeats in the ligand binding domain resembles its counterpart in the human LDL receptor more than it does the other repeats in the shark receptor as suggested by the presence of unique "signature" sequences, indicating that these repeats had already acquired their independent structures by the time of shark development. Furthermore, amino acid sequences of the entire ligand binding domain of shark LDL receptor show 35% identity over a stretch of 294 residues with a Lymnaea stagnalis G-protein-linked receptor (LSGLR). The region of homology between these unrelated proteins includes conservation of most of the unique characteristics of the cysteine-rich repeats of LDL receptor at the expected positions in LSGLR. The results presented are consistent with the hypothesis that all seven repeats in the ligand binding domain of LDL receptor may have been lifted directly from an ancestral gene instead of being evolutionary duplications of a single repeat recruited by the primitive LDL receptor from another gene.

Amino Acid Sequence↗
PubMed1996

Hemodynamic effects of epinephrine, bicarbonate and calcium in the early postnatal period in a lamb model of single-ventricle physiology created in utero.

OBJECTIVES: A reproducible fetal animal model of single-ventricle physiology was created to examine the effects of pharmacologic agents commonly used in the perinatal and perioperative intensive care management of patients with a single ventricle. BACKGROUND: Single-ventricle physiology is characterized by parallel pulmonary and systemic circulations, with effective blood flow to each determined by the relative resistances in the pulmonary and systemic vascular beds. Perinatal and perioperative management of these patients is largely based on empiric observations and differs considerably between institutions and is further complicated by the transitional physiology of the newborn. The lack of animal models of single-ventricle physiology has hindered the understanding of this problem. METHODS: A 10-mm, Damus-Kaye-Stansel-type aortopulmonary anastomosis was created in 10 fetal sheep at 140 +/- 1.2 days of gestation. The main pulmonary artery was ligated distally, and pulmonary blood flow (Qp) was provided through a 5-mm aortopulmonary shunt. Eight lambs were delivered at term and placed on cardiopulmonary bypass (30 min) 48 to 72 h after birth. Pharmacologic interventions (0.1 microgram/kg body weight per min of epinephrine, 2 mEq/kg of sodium bicarbonate and 10 mg/kg of calcium chloride) were performed before and after bypass, and hemodynamic responses were observed. The response to the epinephrine bolus was determined only in the postbypass study. RESULTS: Both before and after bypass, epinephrine infusion and calcium and bicarbonate administration increased Qp and systemic blood flow (Qs) (total cardiac output) but produced only small changes in the Qp/Qs ratio (-0.5% to -7.3% change). With the epinephrine bolus, Qp increased enormously, and the Qp/Qs ratio increased by 584% (p < 0.001). CONCLUSIONS: In neonatal lambs with single-ventricle physiology created in utero, epinephrine infusion and calcium and bicarbonate administration increased total cardiac output without significantly compromising the Qp/Qs ratio. However, epinephrine bolus seems to be hemodynamically detrimental in circumstances of single-ventricle physiology and should be used with caution and probably in relatively lower doses in the resuscitation of patients with single-ventricle physiology. Further investigation of the dose-dependent effects and the effects of prolonged administration of common pharmacologic agents will enable better management of patients with single-ventricle physiology.

Animals↗
PubMed1996

Role of tissue diagnosis in pulmonary involvement in pediatric human immunodeficiency virus infection.

BACKGROUND: Pulmonary complications occur commonly during HIV infection. The aim of this study was to evaluate the clinical value of lung tissue examination in the diagnosis and treatment of pulmonary disorders in children with HIV infection. METHODS: The medical records of 347 children enrolled between January, 1990, and April, 1994, into various antiretroviral therapy protocols were reviewed to identify patients who underwent a lung biopsy. RESULTS: Fourteen patients underwent diagnostic lung biopsies on 16 separate occasions. The most common radiologic findings were nodular infiltrates which were localized in 7 patients and diffuse in 6. Eight patients presented with fever and progressive respiratory distress unresponsive to empiric therapy, whereas the rest had progressive nodular infiltrates. The pathologic diagnoses included opportunistic infection in 7 patients, lymphocytic interstitial pneumonitis in 5, non-Hodgkin's lymphoma in 3 and interstitial fibrosis in 1. The biopsy led to a major change in the treatment of 7 patients which resulted in a significant improvement of the pulmonary process in all of them. In an additional patient the excisional biopsy proved curative. CONCLUSIONS: When patients are selected appropriately, lung biopsy might have a significant impact on therapy and outcome in HIV-infected children with pulmonary infiltrates.

Adolescent↗
PubMed1996

Functional properties of edible mushrooms.

Edible mushrooms such as shiitake may have important salutary effects on health or even in treating disease. A mushroom characteristically contains many different bioactive compounds with diverse biological activity, and the content and bioactivity of these compounds depend on how the mushroom is prepared and consumed. It is estimated that approximately 50% of the annual 5 million metric tons of cultivated edible mushrooms contain functional "nutraceutical" or medicinal properties. In order of decreasing cultivated tonnage, Lentinus (shiitake), Pleurotus (oyster), Auricularia (mu-er), Flammulina (enokitake), Tremella (yin-er), Hericium, and Grifola (maitake) mushrooms have various degrees of immunomodulatory, lipid-lowering, antitumor, and other beneficial or therapeutic health effects without any significant toxicity. Although the data for this functional food class are not as strong as those for other functional foods such as cruciferous vegetables, because of their potential usefulness in preventing or treating serious health conditions such as cancer, acquired immune deficiency syndrome (AIDS), and hypercholesterolemia, functional mushrooms deserve further serious investigation. Additionally, there is a need for epidemiological evidence of the role of this functional food class.

Food↗
PubMed1996

Metastatic gastrinomas: localization with selective arterial injection of secretin.

PURPOSE: To evaluate localization of hepatic metastases with the intraarterial secretin injection test in Zollinger-Ellison syndrome (ZES). MATERIALS AND METHODS: Results in 74 patients with ZES (aged 15-70 years) were retrospectively studied. All patients had undergone computed tomography (CT), magnetic resonance (MR) imaging, ultrasound, abdominal angiography, and an intraarterial secretin test, in which venous blood is sampled periodically after injection of secretin. RESULTS: Twenty-two patients had liver metastases. An increase in venous gastrin concentration of at least 25% at 20 seconds or 50% at 30 seconds after injection indicated a positive result. Results were positive in 41% of patients with and 2% without liver metastases (P < .0001). Sensitivity of the intraarterial secretin test was 41%; of CT and ultrasound, 64%; and of MR imaging and angiography, 77%. Intraarterial secretin test results assisted in clinical management in 22% of patients. CONCLUSION: With the criteria developed, the intraarterial secretin test had high specificity but low sensitivity. It should be used when imaging results are unclear.

Adolescent↗
PubMed1996

Parathyroid adenomas in the aortopulmonary window.

PURPOSE: To describe localization studies in nine patients with ectopic parathyroid adenomas in the aortopulmonary window. MATERIALS AND METHODS: Nine patients with ectopic parathyroid tissue (eight adenomas, one hyperplastic gland) in the aortopulmonary window were examined with ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, and scintigraphy. Diagnostic arteriography (n = 4) and venous sampling (n = 3) were performed in the first four patients; arteriography for the purpose of staining was attempted in the last five patients. RESULTS: The results of CT and MR imaging studies were positive in eight of nine patients (89%) and five of eight patients (63%), respectively. The results of thallium/technetium scintigraphy were negative in three patients scanned (0%), but the results of a repeat study in one patient were positive (33%). Sestamibi scans were positive in six of six patients (100%). Single photon emission CT was performed in all six patients and enabled distinction between adenomas in the aortopulmonary window and those in the thymus. CONCLUSION: Ectopic parathyroid glands in the aortopulmonary window are usually detected at sestamibi scintigraphy, and SPECT is helpful in distinguishing these adenomas from more common adenomas in the anterior mediastinum. CT and MR imaging studies can also enable this distinction, but imaging must extend below the aortic arch.

Adenoma↗
PubMed1996

Altered endothelium-dependent responses in lambs with pulmonary hypertension and increased pulmonary blood flow.

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.

PURPOSE: We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. RESULTS: The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. CONCLUSION: r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

In vitro cytokine profiles and their relevance to rejection following renal transplantation.

Graft rejection remains an important cause of renal allograft failure, despite improvements in immunosuppression and HLA typing. Although HLA matching is beneficial, ensuring an exact match it is often impractical. Thus, a reliable in vitro method for quantitating and qualitating alloreactivity is an important goal. In this study, we measured in vitro the cytokine secretion profiles of mononuclear cells from patients prior to renal transplantation by stimulating with anti-CD3 monoclonal antibody and suppressing with cyclosporine. Mononuclear cells from patients who subsequently developed acute cellular rejection secreted higher mean levels of interleukin (IL)-2 and gamma-interferon (IFN-gamma) than those from patients who had no rejection episodes. IFN-gamma secretion was significantly associated with rejection (P = 0.002), whereas IL-2 secretion did not quite reach statistical significance. There was no significant correlation between IL-4 levels and rejection. Although cyclosporine suppressed the secretion of both IL-2 and IFN-gamma, there was no difference in sensitivity to suppression between rejectors and nonrejectors. These results further emphasize the importance of the TH1 lymphocyte subset in renal allograft rejection. The IFN-gamma secretory capacity of alloreactive T cells may influence the outcome of a renal allograft by (1) activating graft infiltrating macrophages and/or (2) up-regulating HLA molecules on the graft.

Antibodies, Monoclonal↗
PubMed1995

Localization of insulinomas to regions of the pancreas by intra-arterial stimulation with calcium.

OBJECTIVE: To determine the sensitivity of calcium injected into pancreatic arteries in localizing insulin-secreting tumors to regions of the pancreas. DESIGN AND PATIENTS: To stimulate the release of insulin, 25 patients with surgically proven insulinomas (average diameter, 15 mm) had calcium gluconate (0.025 mEq Ca++/kg body weight) injected before surgery into the arteries supplying the pancreatic head (gastroduodenal and superior mesenteric arteries) and the body and tail (splenic artery) of the pancreas. SETTING: Tertiary referral hospital. MEASUREMENTS: Insulin levels were measured in samples taken from the right and left hepatic veins before and 30, 60, and 120 seconds after calcium injection. A twofold increase in insulin level in the sample taken from the right hepatic vein 30 or 60 seconds after injection localized the insulinoma to the segment of the pancreas supplied by the selectively injected artery. Localization done using calcium stimulation was compared with localization done using transcutaneous ultrasonography (n = 22), computed tomography (n = 23), magnetic resonance imaging (n = 21), arteriography (n = 25), and portal venous sampling (n = 9). RESULTS: Calcium stimulation localized 22 of 25 insulinomas (sensitivity, 88% [95% CI, 68% to 97%]) to the correct region of the pancreas. The sensitivities of the other imaging methods were 9% for ultrasonography (CI, 1% to 23%), 17% for computed tomography (CI, 5% to 39%), 43% for magnetic resonance imaging (CI, 22% to 66%), 36% for arteriography (CI, 18% to 57%), and 67% for portal venous sampling (CI, 30% to 93%). Calcium stimulation added only a few minutes to the time needed for pancreatic arteriography and caused no morbid conditions. CONCLUSION: Intra-arterial calcium stimulation with right hepatic vein sampling for insulin gradients is the most sensitive preoperative test for localizing insulinomas.

Adult↗
PubMed1995

Affinity purification of human plasma vitamin D-binding protein.

During the course of our studies to probe the vitamin D ligand-binding domains of vitamin D-binding protein and vitamin D receptor, we developed a synthetic procedure to modify the 3 beta-hydroxyl group of vitamin D3 and its 25-hydroxy- and 1,25-dihydroxy metabolites with a 3'-aminopropylether group. In the present study we have coupled 25-hydroxyvitamin D3-3 beta-3'-aminopropylether to an activated Sepharose matrix. Using this stable and reusable affinity matrix we have purified human vitamin D-binding protein from human plasma to homogeneity.

Binding Sites↗
PubMed1995

Impact of recounting trauma stories on the emotional state of Cambodian refugees.

Twenty Cambodian refugees with premigration histories of trauma received an average of 16 sessions of individual therapy from a Cambodian bicultural counselor at a trauma treatment center in Sydney, Australia. Nineteen of the 20 patients reported that during treatment they had been willing to talk about their trauma histories, a finding that raises doubts about the commonly held belief that Asians are not psychologically minded and avoid disclosing emotionally sensitive information to health care workers. However, self-disclosing therapy alone did not appear to benefit these patients. Only four patients found talking about their trauma story directly helpful in improving their emotional state, and three of the four found the relief to be transitory.

Adaptation, Psychological↗