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Biomedical subjects

K Y Ng

Publications and source records attributed to K Y Ng.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of vascular permeability factor on the permeability of cultured endothelial cells from brain capillaries.

The effects of vascular permeability factor (VPF) on the blood-brain barrier (BBB) permeability were studied in cultured capillary endothelial cells from bovine brain. When VPF was added to the abluminal or brain side of the BBB, a rapid increase in the BBB permeability was observed. This increase in the BBB permeability is dependent on the concentration of the VPF used and is reversible on removal of the VPF. Contrarily, when VPF was added to the luminal or blood side of the BBB, no increase in the BBB permeability was observed. These results suggest that the receptors for VPF are located on the abluminal side of the BBB.

Animals↗
PubMed1998

Murine MPS I: insights into the pathogenesis of Hurler syndrome.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme alpha-L-iduronidase. A murine model which shows complete deficiency in alpha-L-iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long-term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM2 and GM3 gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.

Animals↗
PubMed1996

Biochemical characteristics of a primary blood-brain barrier cell culture system as a function of the activity of the proteases used in tissue disaggregation.

Utilization of primary cultured brain capillary endothelial cells (BCECs) as an in vitro model of the blood-brain barrier (BBB) depends on the extent to which cultured BCECs retain the in vivo characteristics. Recently, we have reported that consistent isolation of BCECs that mimic the in vivo BBB depends on whether a specific ratio between the weight of the isolation enzyme (collagenase/dispase) and the weight of the capillaries present during the isolation is used. Since it is possible for the same weight of an enzyme to possess different activity levels, it is felt that activity rather than weight of an enzyme should be used in arriving at the above ratio. Therefore, using bovine brain as the source of BCECs, we have quantified the amount of collagenase/dispase needed for optimal isolation of BCECs and retention of their phenotypic properties in terms of collagenase/dispase activity per g of capillaries. Monolayers of bovine BCECs isolated at 0.15 or 0.30 units of collagenase and 2.06 or 4.12 units dispase per g of capillaries gave the best overall quality as judged by their permeability characteristics and the activities of angiotensin converting enzyme, alkaline phosphatase and gamma-glutamyl transpeptidase.

Alkaline Phosphatase↗
PubMed1996

Hepatic manifestation of malignant histiocytosis: a case study.

Malignant histiocytosis, as defined by Rappaport, is now known as a manifestation of malignant lymphoma, the majority of which is the T-cell type. However, unlike the typical presentation of most non-Hodgkin lymphomas, this condition presents with atypical features mimicking acute hepatitis or infectious mononucleosis. The latter diagnosis is often made because of the occurrence of atypical mononuclear cells on the peripheral blood films. This is clearly seen in the seven patients we report where the initial diagnoses were that of viral fever or hepatitis. Some characteristics were found in these patients to differentiate the condition from infectious mononucleosis (IMS) and acute hepatitis (AH): paucity of lymph nodes, cholestasis and prolonged prothrombin time (PT) which is atypical IMS; persistent fever, thrombocytopaenia and disproportionately high aspartate aminotransferase which is unusual in AH in the absence of any drug or alcohol history. The PT is the most important prognosis factor. Early diagnosis and treatment led to improved survival in an otherwise aggressive and rapidly fatal condition.

Acute Disease↗
PubMed1995

Peptidyl dipeptidase A-catalyzed metabolism of delta sleep-inducing peptide in bovine brain microvessel endothelial cells: a cell culture model of the blood brain barrier.

Previous studies have shown that the metabolism of delta sleep-inducing peptide (DSIP) in the blood-brain barrier (BBB) is catalyzed by amino-peptidases. In this study, we have shown that peptidyl dipeptidase A in cultured bovine brain microvessel endothelial cells (BBMEC), a model of the BBB, and a purified form of this enzyme can also metabolize DSIP by sequential hydrolyses of dipeptides or tripeptides from the carboxyl terminus of this nonapeptide. Both the dipeptidase and tripeptidase activity associated with peptidyl dipeptidase A can be inhibited by captopril. Total stabilization of DSIP to metabolism in BBMEC could be achieved by inclusion of an inhibitor of peptidyl dipeptidase A (e.g., captopril) and an inhibitor of aminopeptidases (e.g., bestatin).

Amino Acid Sequence↗
PubMed1994

Partial sequence analysis of the hepatitis C viral genome in Singapore patients.

The distribution of hepatitis C viral (HCV) genotypes in Singapore has not been previously determined. We studied the sera of 40 Singapore patients which were PCR-positive for HCV. The HCV genotypes were determined by direct sequencing of amplified sequences of the 5' non-coding region, after reverse transcription. Of the 40 samples, 35/40 (87.5%) were of HCV type 1, 2/40 (5.0%) were of type 2 and 3/40 (7.5%) were of type 3. The most common HCV genotype in this study was the type 1 genotype. Our results confirm the wide geographical distribution of HCV genotypes.

Hepacivirus↗
PubMed1994

Evaluation of a vitamin-cloaking strategy for oligopeptide therapeutics: biotinylated HIV-1 protease inhibitors.

The outstanding limitations to the oligopeptide as a therapeutic agent are poor oral availability and rapid biliary clearance. To address these concerns a series of eight peptidic HIV-1 protease inhibitors containing the structural segment of the vitamin biotin have been prepared. These have been evaluated with regard to the hypothesis that this vitamin would cloak the peptidic character of these oligopeptides, and thus impart to these inhibitors the potential for absorption and distribution via biotin transporters and receptors. By iterative optimization about a -Cha psi[CH-(OH)CH(OH)]Val- core inhibitory insert, three particularly potent inhibitors (K(i) < or = 10 nM) of the HIV-1 protease were obtained. Although excellent cell culture antiviral activity is observed for other peptidic protease inhibitors of comparable affinity, none in this series exhibited satisfactory antiviral activity. This failure is attributed to the incompatibility of the hydrophilic and hydrogen-bonding biotin segment, with the facile membrane permeability and intracellular access presumably required for antiviral activity. The ability of the biotin to cloak the peptide, and thus render the overall appearance of the conjugate as that of a vitamin, was evaluated. Four of this series were evaluated for recognition by the Caco-2 cell intestinal biotin transporter. None inhibited competitively biotin uptake, indicating a lack of recognition. A vitamin may bind to a specific protein carrier, and thus attain an improved serum profile (by resistance to biliary clearance) and advantageous delivery to cells. Therefore, the serum concentrations of three were evaluated following an iv bolus in a rat model for serum clearance. One of the three protease inhibitors (L-idonamide, 6-cyclohexyl-2,5,6-trideoxy-2-(1-methylethyl)-5-[[3-methyl-1-oxo-2-[[5- (hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-1- oxopentyl]amino]butyl]amino]-N-[2-methyl-1-[[(2- pyridinylmethyl)amino]carbonyl]butyl]-, [3aS-[3a alpha, 4 beta (1R*,2R*,3R*),6 alpha]]-) sustained a more than 5-fold increase in serum concentration at all time points relative to the benchmark structure. The remaining two had serum concentrations at least equal to the benchmark, suggestive of improved resistance to clearance. One (L-idonamide,6-cyclohexyl-2,5,6-trideoxy-5-[[2-[[5-(hexahydro-2-ox o-1H- thieno-[3,4-d]imidazol-4-yl)pentyl]thio]benzoyl]amino]-2-(1- methylethyl)-N-[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]-, [3aS-[3a alpha, 4 beta(1R*,2R*),6a alpha]]-) was prepared as a complex with the biotin-binding protein avidin. Avidin may resemble an endogenous serum biotin carrier protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides.

With the exception of various central nervous system (CNS)-required nutrients for which specific, saturable transport systems exist, the passage of most water-soluble solutes through the blood-brain barrier (BBB) is believed to depend largely on the lipid solubility of the solutes. Most peptides, therefore, do not enter the CNS because of their hydrophilic character. Recently, utilizing homologous series of model peptides and Caco-2 cell monolayers as a model of the intestinal mucosa, it was concluded that the principal determinant of peptide transport across the intestinal cellular membrane is the energy required to desolvate the polar amide bonds in the peptide (P. S. Burton et al., adv. Drug Deliv. Rev. 7:365, 1991). To determine whether this correlation can be extended to the BBB, the permeabilities of the same peptides were determined using an in vitro as well as an in situ BBB model. The peptides, blocked on the N- and C-terminal ends, consisted of D-phenylalanine (F) residues: AcFNH2, AcF2NH2, AcF3NH2, AcF2(NMeF)NH2, AcF(NMeF)2NH2, Ac(NMeF)3NH2, and Ac(NMeF)3NHMe. A good correlation among the permeabilities of these model peptides across the bovine brain microvessel endothelial cell (BBMEC) monolayers, an in vitro model of the BBB, and their permeabilities across the BBB in situ was observed (r = 0.928, P < 0.05). The permeabilities of these peptides did not correlate with the octanol-buffer partition coefficients of the peptides (r = 0.389 in vitro and r = 0.155 in situ; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Biotin transport in a human intestinal epithelial cell line (Caco-2).

The apical (AP)-to-basolateral (BL) transport of [3H]biotin across Caco-2 cell monolayers grown on a Transwell polycarbonate membrane was shown to be dependent on days in culture, reaching a maximum at 10 days. The AP-to-BL transport of [3H]biotin was always much greater than the BL-to-AP transport. AP-to-BL transport of [3H]biotin was concentration-(Km = 1.49 microM and Vmax = 1.86 pmol.mg protein-1.minute-1), temperature-, Na(+)- and energy-dependent, and proceeded against a concentration gradient in the BL side. [3H]Biotin transport was inhibited by unlabeled biotin and several structural analogues (e.g., desthiobiotin and biotin methyl ester) but not by taurocholic acid. No metabolism of [3H]biotin was detected in the AP-to-BL transport across Caco-2 cell monolayers. This study demonstrates that [3H]biotin transport in Caco-2 cells occurs by a carrier-mediated process.

Biological Transport, Active↗
PubMed1993

Relapsing pancreatitis due to juxta-pancreatic duodenal duplication cyst with pancreatic ductal communication.

A 21 year old patient first presented with acute pancreatitis in infancy, followed by subsequent episodes of relapsing pancreatitis in childhood. The cause of the pancreatitis defied diagnosis, despite two laparotomies in infancy and childhood, until twenty years later when a juxta-pancreatic duodenal duplication--a rare congenital lesion--was finally discovered. The duplication communicated with the main pancreatic duct via a long, aberrant duct, resulting in the relapsing pancreatitis. Abdominal ultrasonography and computerized tomography scan, and endoscopic retrograde cholangiopancreaticogram were useful in demonstrating the lesion. Surgical excision of part of the cyst, with marsupialization of the remaining structure to the stomach, abolished further symptoms and recurrence of pancreatitis.

Adult↗
PubMed1993

Doppler sonographic detection of reverse twin-twin transfusion after intrauterine death of the donor.

We report a "stuck" twin, in which a reverse blood shunt from the recipient to the donor was detected by Doppler sonography after death of the donor. This acute reverse transfusion caused intrauterine fetal distress and severe neonatal anemia of the surviving recipient. We believe that acute hemodynamic change after death of one fetus, in addition to causing a derangement in coagulation, causes immediate danger or subsequent organ damage for the surviving co-twin.

Adult↗
PubMed1993

Hydatidiform mole and post-evacuation regression patterns of serum beta human chorionic gonadotrophin.

Eighty-nine patients who had hydatidiform moles evacuated at the General Hospital, Kuala Lumpur, were followed with serum beta hCG determinations from October 1988 to June 1991. A regression curve for serum beta hCG, as measured by RIA, was derived from the results of 47 of the patients who demonstrated spontaneous regression of serum beta hCG titres. All 47 patients had normal serum titres at 135 days after evacuation. The mean time taken to reach normal level was 82.6 days, while the range was 39 to 135 days (5 to 19 weeks).

Adult↗
PubMed1992

Mixtures of tight-binding enzyme inhibitors. Kinetic analysis by a recursive rate equation.

When two or more tight-binding inhibitors are present in an enzyme assay, the equation that relates the initial velocity v to the concentration of reactants cannot be written in an algebraically explicit form. Rather, for n inhibitors it is an implicit polynomial equation of degree n + 1 with respect to v. The complexity of the polynomial coefficients dramatically increases with each added inhibitor. Solving the transcendental rate equation by traditional methods of numerical mathematics has proven tedious because of the sensitivity of these methods to initial estimates and because of the existence of multiple roots. However, the equation can be rearranged into a convenient recursive form, one in which the velocity appears on both sides and the solution is found iteratively. The algebraic form of the recursive rate equation is remarkably simple and differs from the rate equation for classical rather than tight-binding inhibition only by an added term. The numerical stability and the speed of convergence were tested on the case of two competitive inhibitors. Initial estimates of velocity that spanned 12 orders of magnitude converged within five iterations. The velocities computed with the recursive method for a single tight-binding inhibitor were identical with the values predicted by the Morrison equation. The method is used to analyze experimental data for the inhibition of rat liver dihydrofolate reductase by mixtures of the anticancer drug methotrexate and its metabolic precursor form, methotrexate-alpha-aspartate (a prodrug).

Animals↗
PubMed1992

Successful treatment of two viable tubal pregnancies by two-step local injection.

Two viable tubal pregnancies were diagnosed by transvaginal ultrasound with a serum beta-hCG level of up to 3,004 mIU/mL in Case 1 and 16,676 mIU/mL in Case 2. Under transvaginal sonographic guidance, a local injection of potassium chloride (0.5 mL = 1.0 mEq) into the embryo was performed for the purpose of embryocide. In Case 1, a follow-up of serum beta-hCG levels showed an initial plateau and subsequent regression to negative, 49 days after the local injection. However, a persistent increase in serum beta-hCG levels was noted in Case 2 for two samples at intervals of two days during follow-up, 27,800 and 36,500 mIU/mL, in spite of the fact that no fetal cardiac activity was visible. Six days later, laparoscopy was done and methotrexate, 50 mg in 6 mL of normal saline, was injected into the ampullar mass of the right fallopian tube in two divided dosages. The serum beta-hCG levels then gradually decreased and returned to negative 60 days after the methotrexate injection. For a viable ectopic pregnancy, this new modality of two-step local injection, first with potassium chloride and then with supplemental methotrexate, separately by two procedures, may offer an additional choice of conservative treatment.

Adult↗