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Biomedical subjects

K Wong

Publications and source records attributed to K Wong.

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

Pituitary adenoma as an unsuspected clival tumor.

Pituitary adenomas are common tumors that account for about 10% of intracranial neoplasms. Most arise from the adenohypophysis and are confined to the region of the sella turcica. Other sites may be involved as a result of extension, infiltration, or ectopic location. However, posterior extension or ectopic involvement of the clivus of the sphenoid and occipital bones is rare. Seven patients with destructive clival masses were referred to our institution with presumptive diagnoses of chordomas. In all cases, histologic workup revealed pituitary adenomas. Because they represent a subset of adenomas, the histologic features of the tumors were studied, and the clinical histories of the patients were reviewed. Five of the patients were men, aged 31 to 67 years, and two were women, aged 55 and 67 years. Four patients had extremely high plasma concentrations of prolactin (8,132-22,424 ng/ml, nl < 15). Four tumors resembled usual sellar adenomas; however, three exhibited nuclear pleomorphism, mitotic figures, and other morphologic features, suggesting alternate diagnoses. Three required immunoperoxidase stains in addition to those for pituitary hormones, and three required electron microscopy for diagnosis. Destructive invasion of the clivus by pituitary adenomas is rare, and anaplastic features of some of the tumors may lead to difficult diagnoses.

Adenoma↗
PubMed1995

Treatment of acute promyelocytic leukaemia in first relapse with all-trans retinoic acid.

A 27-year-old Chinese woman with acute promyelocytic leukaemia in first relapse after the initial conventional induction chemotherapy 18 months earlier was treated with all-trans retinoic acid (ATRA) at an initial dose of 45 mg/m2 and subsequently increased to 65 mg/m2 on day 15. Complete remission was achieved after a total of 40 days of ATRA alone. Serial marrow examinations during induction showed progressive maturation of myelopoiesis without bone marrow hypoplasia. There was a significant reduction in number of cells with the t(15;17) translocation when complete remission was achieved. ATRA was very well-tolerated. The symptoms of dry skin and intermittent headache were self-limiting.

Adult↗
PubMed1994

Cathepsin B, a cysteine protease implicated in metastatic progression, is also expressed during regression of the rat prostate and mammary glands.

We have developed a novel library-to-library cross-screening technology to clone unique mRNAs that are expressed during tissue regression. We have cloned a number of regression selected genes (RSG) that are expressed during the regression of the mammary gland and ventral prostate of the rat after the removal of the respective trophic hormone. In this investigation, we have characterized one of these genes, RSG-2, that is homologous to cathepsin B, a thiol protease that has been previously identified as one of the extracellular proteases which is activated in metastatic cells. The steady-state levels of RSG-2 mRNA in the normal prostate are low but detectable. In the regressing prostate, RSG-2 mRNA levels peak at 3-4 days after castration, at the time that tissue regression is maximal. The gene is induced in a similar fashion in the regressing mammary gland. Using in situ hybridization, we have established that RSG-2 mRNA is expressed in the luminal epithelial cells of the prostate and mammary gland that are known to undergo active cell death, suggesting that it may be a general marker for secretory epithelial cell death. Analysis of the distribution of the cathepsin B protein by immunofluorescence microscopy demonstrates that there is diffuse, but punctate, expression of the protein in all of the luminal epithelial cells of the normal prostate and mammary gland. However, at early times after hormone ablation in both glands, the majority of the increase in cathepsin B protein appears to result from redistribution to the basal aspect of the cells. At later time points, there appears to be increased amounts of the protein which is localized to the apoptotic bodies. These results suggest that RSG-2, or cathepsin B, is required for the local degradation of the basement membrane, which is one of the earliest morphologically recognizable events of active cell death.

Amino Acid Sequence↗
PubMed1994

Cloning and characterization of a human phosphatidylinositol 4-kinase.

Phosphatidylinositol (PtdIns) 4-kinase catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Here we report the first mammalian cDNA clone of a PtdIns 4-kinase (named PI4K alpha). The 2.6-kb cDNA encodes a protein of 854 amino acids that is highly homologous to the recently cloned yeast PtdIns 4-kinase STT4 and is also homologous to a second yeast PtdIns 4-kinase, PIK1. PI4K alpha has more distant sequence homology to the catalytic domains of mammalian and yeast PtdIns 3-kinases and to the yeast Tor family of proteins. It also has a region of similarity to pleckstrin homology domains and a potential ankyrin repeat. Cross-hybridizing messages were detected in all human tissues investigated. The enzymatic properties of the protein expressed in insect cells are characteristic of type II PtdIns 4-kinases (activated by detergent and inhibited by adenosine), and PI4K alpha is recognized by an antibody specific for type II PtdIns 4-kinases.

1-Phosphatidylinositol 4-Kinase↗
PubMed1994

Pharmacological assessment of spantide II analogues.

We have studied the structure-activity relationship of a series of tachykinin receptor antagonists based on spantide II. Fifteen novel peptides were tested for their ability to antagonize the electrically evoked tachykinin receptor-mediated response in the isolated rabbit iris sphincter muscle. Substitution or deletion of one to three amino acids in the spantide II sequence caused significant changes in biological activity. Eight of the novel analogues were found to be as potent as or more potent than spantide II and some were found to have better water solubility. We tested the selectivity for different tachykinin receptors of spantide II and two of the eight most potent analogues. They all interacted with tachykinin NK1 (rabbit jugular vein) and tachykinin NK2 (rabbit pulmonary artery) receptors with pA2 values of about 6.5-7.5 at the NK1 receptor and of 5.9-7.2 at the NK2 receptor, while being inactive at the tachykinin NK3 receptor (rat portal vein). Spantide II and the novel analogues were without effect on electrically evoked cholinergic responses of the isolated rabbit iris sphincter and on electrically evoked sympathetic responses of the guinea-pig vas deferens; moreover, they were without local anaesthetic-like effects on action potentials of the frog sciatic nerve, which suggests that they do not produce a general neurosuppressive effect. They were as effective as or slightly less effective than spantide II in causing histamine release from rat peritoneal mast cells.

Action Potentials↗
PubMed1994

Liposome-complement interactions in rat serum: implications for liposome survival studies.

Serum complement opsonizes particles such as bacteria for clearance by the reticuloendothelial system. Complement has been reported to interact with liposomes and therefore may mediate the reticuloendothelial system clearance of liposomes. This study has used a rat serum model to define some of the characteristics of liposomes which modulate their ability to activate complement. Using functional hemolytic assays and C3/C3b crossed immunoelectrophoresis, we have demonstrated that liposomes activated rat complement in a dose-dependent manner with higher concentrations of liposomes activating higher levels of complement. The detection of complement activation required the inclusion of phospholipids bearing a net charge. Complement activation occurred via the classical pathway; no alternative pathway activation was detected. The presence of cholesterol contributed to complement activation in a dose-dependent manner. Phospholipid fatty acyl chain length did not influence complement activation while the introduction of unsaturated acyl chains markedly decreased levels of complement activation. Liposome size also influenced complement activation with 400 nm unilamellar vesicles more effectively activating complement than 50 nm vesicles for equivalent amounts of exposed lipid. These studies demonstrate that the composition of the liposome greatly affects the in vitro activation of rat serum complement and suggest that the biological half-life of liposomes in the circulation of rats may be altered by changing the liposome composition to reduce complement activation.

Animals↗
PubMed1994

Staurosporine induces hydrolysis of phosphatidyl inositol 4,5-bisphosphate in human platelets.

Staurosporine in the micromolar range raised inositol trisphosphate in intact human platelets to levels comparable to that mediated by thrombin. This response was inhibited by neomycin, a phospholipase C antagonist. Staurosporine alone induced a weak, transient rise in cytosolic free calcium levels ([Ca2+]i) from release of internal Ca2+ stores but potentiated the effect induced by thrombin. Therefore, it is unlikely that this alkaloid suppressed inositol trisphosphate mobilization of Ca2+. Additional studies show that staurosporine, 0.5-5 microM, stimulated GTPase activity in platelet membranes while 2 microM K252a and 20 microM H7 were inactive. Present results suggest that staurosporine may activate platelet phospholipase C at the level of G proteins or receptors.

Alkaloids↗
PubMed1994

Induction of gene expression during involution of the lactating mammary gland of the rat.

After weaning, the mammary gland ceases lactation and involutes. The wet weight of the gland decreases by 70% within 4 days of weaning. This involves significant tissue remodelling as the ducts regress and return to the resting state. The presence of apoptotic bodies in the luminal epithelial compartment 2 to 3 days after weaning provides clear evidence that a substantial proportion of the regression is attributable to the induction of active cell death (ACD) of the epithelial cells. These changes in the architecture of the gland were found to be mirrored by changes in gene expression. The steady-state level of beta-casein mRNA decreased rapidly after weaning from the high levels seen during lactation to undetectable levels by 8 days after weaning. The steady-state levels of expression of a number of genes associated with ACD, including TRPM-2, tissue transglutaminase (TGase) and poly(ADP-ribose) polymerase (PARP), increased transiently during this time-frame. The steady-state level of TRPM-2 mRNA increased 2 days after weaning, reaching a peak on day 4, and decreasing to undetectable levels by day 8 after weaning. The steady-state levels of two other mRNAs, TGase and PARP, showed very similar kinetics. In contrast, the mRNA for Hsp 27, which has been shown to be induced during prostate regression, was not significantly induced in the regressing mammary gland. In-situ hybridization demonstrated that the TRPM-2, TGase and PARP genes were expressed predominantly in the luminal epithelial cells of the ducts. These cells expressed beta-casein mRNA during lactation, and underwent ACD after weaning. While the ultrastructural changes in the mammary gland after weaning, and the induction of TRPM-2, TGase and PARP mRNAs, are reminiscent of apoptosis in the prostate, several features of the process are different. Most notably, the disruption of the secretory processes and the lack of increased expression of Hsp 27 in the regressing mammary gland suggest that there may be a number of important events in ACD that are not common to all cells.

Animals↗
PubMed1994

Multiple myeloma: the National University Hospital (NUH) experience.

The aim of this retrospective study was to define the characteristics of local patients with multiple myeloma. Twenty-nine de novo cases were accrued from October 1986 to January 1992 at the National University Hospital of Singapore. Features like median age of presentation, sex distribution, the incidence of IgG, IgA and light chain subtypes were similar to published data. However IgD myeloma appeared to be more common here and it tended to be more advanced at presentation. Objective response rate to treatment with the melphalan-prednisolone combination was about 40% with a median survival of 18 months.

Adult↗
PubMed1994

Evaluation of unstented aortic homografts for the treatment of prosthetic aortic valve endocarditis.

BACKGROUND: Prosthetic aortic valve endocarditis is a serious complication that carries a high morbidity and mortality. Aortic homografts have been used in this setting, but long-term results are not available. METHODS AND RESULTS: Over a 23-year period, 48 patients presented with infected aortic valve substitutes: 28 homografts, 15 mechanical, and 5 xenografts. Nineteen patients had emergency surgery, and the mean interval between the first and second operation was 5.9 years (range, 1 month to 22 years). In 28 patients, the preoperative New York Heart Association (NYHA) class was III or IV. Active endocarditis was present in 39 patients, and the microorganisms grown were Staphylococcus epidermidis (n = 13), Staphylococcus aureus (n = 6), Streptococcus viridans (n = 6), Streptococcus faecalis (n = 4), Candida albicans (n = 5), and Gram-negative spp (n = 2). Aortic root abscesses were found in 28 (58%) patients, and transesophageal echocardiography was 95% accurate in their localization. All patients received homograft aortic valves, 19 as root replacement and 29 using the freehand technique. There were four (8.3%) early deaths; poor left ventricular function and concomitant procedure were identified as risk factors. At a mean follow-up of 4 years (range, 2 months to 19 years) 95% of the patients were in NYHA class I or II without significant aortic regurgitation. The actuarial survival at 5 years was 97% (confidence limit, 84% to 100%), and freedom from endocarditis at 10 years was 97% (confidence limit, 84% to 100%). Multivariate analysis did not identify risk factors for these late events. CONCLUSIONS: Homograft aortic valves offer good early and long-term results in patients with infected aortic valve substitutes.

Actuarial Analysis↗
PubMed1994

The use of unstented homograft valves for aortic valve reoperations. Review of a twenty-three-year experience.

Unstented homograft valves offer several theoretical advantages when used for patients who have had previous operations on the aortic valve. Between January 1970 and February 1993, 177 patients received unstented homograft valves after previous aortic valve operations. One hundred thirty-four patients had previous aortic valve replacement in the form of homografts (101 patients), mechanical prostheses (24 patients), and bioprostheses (9 patients), and 43 had previous valve repair. The indication for reoperation was deterioration of a noninfected valve (124 patients), infective endocarditis (40 patients), and failure of a noninfected mechanical valve (12 patients). Fresh homograft valves were implanted in 60 patients, homografts preserved in antibiotics were used in 111 patients, and 6 patients received cryopreserved valves. Aortic valve and root replacement was performed in 60 patients, and in 117 the homograft was inserted freehand in the subcoronary position. The early mortality was 5.1%. The actuarial survival at 10 years was 71%. Multivariate analysis demonstrated that patients with previous homograft replacement have a better long-term survival than patients who had previous mechanical valves (p = 0.017). The freedom from valve-related death and reoperation was 70% at 10 years. Fresh homografts faired better than antibiotic-sterilized homografts (p = 0.007). None of the patients had recurrence of endocarditis at 6 months, although 1 patient died of uncontrolled infection despite valve replacement. The freedom from recurrent endocarditis was 88% at 10 years. We conclude that unstented aortic homografts provide good early and long-term results for aortic valve reoperations, particularly in patients with previous homograft replacement. Recurrent endocarditis is uncommon even in patients operated on for prosthetic valve infections.

Adolescent↗
PubMed1993

Mutational analysis of the intracellular domain of the human growth hormone receptor.

The human growth hormone (GH) receptor contains an extracellular hormone-binding domain of about 246 amino acids, a single transmembrane domain, and a cytoplasmic region of 350 residues. X-ray crystallographic and functional data show that a single GH molecule dimerizes two receptors to initiate receptor signaling. We have constructed a series of truncations of the cytoplasmic domain of the human GH receptor and have examined the function of these truncated receptors by expressing them in the interleukin-3-dependent promyeloid cell line, FDC-P1. When transfected with a functional GH receptor, these cells grow in the presence of GH without interleukin-3. We find that truncated GH receptors containing as few as 54 amino acids of the cytoplasmic domain are able to transmit a GH proliferative signal; thus, at least 84% of the intracellular domain is unnecessary for signaling in this system. The 54-amino-acid region contains a proline-rich sequence that is found in a similar location in most other members of the GH/cytokine receptor family. Perhaps, this sequence is directly involved in the signaling process mediated by this receptor family.

Amino Acid Sequence↗
PubMed1993

Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis.

It is well established that chronic ethanol ingestion enhances lipid peroxidation in the liver in vivo and in vitro. The relationship of lipid peroxidation and protein adduct formation to morphologically assessed liver damage remains problematic. To help determine if a relationship exists between lipid peroxidation and liver pathology rats were fed ethanol and a high fat diet by continuous intragastric tube feeding for 72 days, maintaining the blood alcohol levels above 200 mg/dl. This model induced a fatty liver with focal necrosis and fibrosis. This pathology was associated with an increased total cytochrome P450, an increased cytochrome P450 2E1 isoenzyme (CYP2E1), a decrease in the NADPH-cytochrome P450 reductase activity, an increased rate of NADPH oxidation and an increased NADPH-dependent lipid peroxidation in liver microsomes compared to controls. Serum protein adducts with malondialdehyde 4-hydroxynonenal were significantly increased. Thus, the alcohol-induced liver pathology was associated with the induction of CYP2EI, lipid peroxidation, and protein adduct formation. When isoniazid (INH) in therapeutic doses was fed to rats with ethanol these parameters were changed in that central-central bridging fibrosis was increased, as was lipid peroxidation, whereas INH reduced the ethanol-induced decrease in the reductase, the increase in total P450 and CYP2EI, as well as the NADPH oxidation rate and the elevation of serum transaminase levels. The results tend to link central-central bridging fibrosis with increased lipid peroxidation and aldehyde-protein adduct formation caused by ethanol.

Aldehydes↗
PubMed1993

Sphingosine mobilizes intracellular calcium in human neutrophils.

The effect of sphingosine on the cytosolic free Ca2+ concentrations, [Ca2+]i, of human neutrophils was re-examined using Fura-2 loaded cells. We found that sphingosine induced a dose-dependent elevation of [Ca2+]i. At sphingosine concentrations > or = 10 microM, the rise in [Ca2+]i was biphasic; an initial phase increasing basal [Ca2+]i by 100% was succeeded by a second phase which raised [Ca2+]i to several microM. The enhanced signal was sustained and slowly approached the Fmax of Fura-2 over 10 min. Although cytotoxicity assays indicate that Fura-2 leakage contributed to the rise in fluorescence, EGTA, surprisingly, had no effect on the time course of this response. The explanation was that EGTA blocked Fura-2 leakage from and trypan blue uptake by neutrophils. Thus, in the presence of EGTA, biphasic increases in the fluorescent signal can be attributed mainly to release of intracellular Ca2+. Mn2+ quenching studies confirmed that sphingosine mobilized Ca2+ in two distinct phases and promoted the influx of Mn2+. Mn2+ entry, however, was not matched by substantial Ca2+ influx. Sphingosine elevation of [Ca2+]i was insensitive to pertussis toxin treatment of neutrophils and was not correlated with (1,4,5)IP3 formation. Studies with semi-permeabilized cells show that sphingosine, up to 80 microM, neither mobilized Ca2+ significantly nor inhibited active Ca2+ sequestration. Sphingosylphosphorylcholine induced a small but dose-dependent release of Ca2+. We hypothesize that a metabolite of sphingosine may release Ca2+ directly in intact neutrophils.

Biological Transport↗
PubMed1993

On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: drug structure-activity studies on isolated peripheral nerve.

Impulse inhibition by local anesthetics (LAs) is potentiated by extracellular solutions containing HCO3-. CO2 (BC), relative to the inhibition in BC-free solutions at the same pH. We studied the mechanistic basis of this potentiation by assaying compound action potential amplitudes in desheathed frog sciatic nerves with the sucrose-gap method. We compared the potencies of 12 different impulse-blocking agents in Ringer's buffered with BC (BC-R) and in Ringer's containing only atmospheric CO2 and buffered by a zwitterionic compound (3-(N-morpholino)propanesulfonic acid-Ringer's). The relative inhibition produced by an agent in BC divided by the inhibition produced in 3-(N-morpholino)propanesulfonic acid, was defined as the potentiation factor (PF). The organic guanidinium blockers of sodium channels, tetrodotoxin and saxitoxin, which act at a different site from that for LAs, were, by our definition, nominally potentiated (PF = 1.33 +/- 0.04, mean +/- SEM, n = 4, and 1.24 +/- 0.07, n = 10, respectively), implying that BC induces a decrease in the safety margin for impulse conduction, a decrease that cannot itself alone account for the much larger potentiation (PF = 5-8) by BC observed with certain LAs. Only nominal potentiations occurred with charged LAs (PF = 1.15), showing that little direct potentiation of the cationic LA species per se occurs. Inhibition by the permanently neutral LA benzocaine had a significantly larger than nominal potentiation (PF = 1.8) showing that BC can potentiate neutral LAs. Among the tertiary amine LAs, potentiation of ester-linked drugs (procaine, RAG505; PF = 3.9, 5.4, respectively), exceeded that of their amide-linked homologues (procainamide, lidocaine; PF = 1.3, 2.8, respectively) which have higher pKa values. This result is consistent with an ion trapping mechanism whereby CO2 acidifies the axoplasm and thereby increases the concentration of protonated LA inside the nerve fibers. However, slight differences in the molecular structure of 3 degrees-amine LAs with similar pKa values resulted in significantly different potentiations (e.g., procaine, PF = 3.9; 2-chloroprocaine, PF = 8.7), suggesting that the HCO3- or CO2 molecules interact specifically with the LA molecule or with LA binding sites in the nerve membrane. Spectrophotometric measurements of the free [Ca2+] in Ringer's showed it to be similar (+/- 0.03 mM) for both buffers, obviating changes in extracellular Ca2+ as a mechanism of BC potentiation. The resting potential of the nerve was slightly more negative (approximately -4 mV) in BC-R, so membrane depolarization cannot explain the potentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗