Biomedical subjects

S Ng

Publications and source records attributed to S Ng.

At least 19 recordsLinked to original sources

PubMed2003

A phase I dose-escalation study of docetaxel with granulocyte colony-stimulating factor support in patients with solid tumours.

BACKGROUND: Docetaxel is a widely active cytotoxic agent. The principal dose-limiting toxicities (DLTs) of the 3-weekly regimen are neutropenia and febrile neutropenia. Use of prophylactic granulocyte colony-stimulating factor (G-CSF) may allow higher doses of docetaxel to be administered with potentially greater anticancer efficacy. The objectives of this study were to determine the maximum tolerated dose (MTD) and toxicity profile of docetaxel given with G-CSF support. PATIENTS AND METHODS: Eligible patients had solid tumours and were aged 18-75 years with a WHO performance status of up to 2. Strict criteria for liver function were followed. Patients may have received one previous regimen of chemotherapy in addition to adjuvant chemotherapy. Cohorts of three to six patients received docetaxel over 60-90 min every 3 weeks, commencing at 110 mg/m(2) and escalating at 10 mg/m(2) increments. Patients also received G-CSF 5 micro g/kg/day until neutrophil recovery. A 3-day corticosteroid prophylaxis was given. RESULTS: Twenty-nine patients with median age 55 years (range 29-75) were included. Fourteen (48%) had previously received chemotherapy. At the 170 mg/m(2) dose level (the MTD), two of three patients had DLTs and 160 mg/m(2) was determined to be the recommended dose. The principal DLTs were skin and neurosensory toxicity. Asthenia was frequent, especially at dose levels >/=140 mg/m(2). Grade 4 neutropenia occurred in only 10 patients (35%) and was not dose related, with febrile neutropenia in three patients (10%). CONCLUSIONS: Docetaxel may be escalated considerably above standard doses when administered with G-CSF support. The recommended dose for phase II studies is 160 mg/m(2). With escalated-dose docetaxel, DLTs were non-haematological and qualitatively similar to the toxicity profile at standard doses.

Adult↗

PubMed2002

Further evidence for the decay K+ -->pi+nu(nu).

Additional evidence for the rare kaon decay K+-->pi+nu(nu) has been found in a new data set with comparable sensitivity to the previously reported result. One new event was observed in the pion momentum region examined, 211 pi+nu(nu)) = 1.57(+1.75)(-0.82)x10(-10).

Journal Article↗

PubMed2002

Multi-centre assessment of the Spiegelberg compliance monitor: interim results.

Analyses of a multi-centre database of 71 patients at risk of raised ICP showed that in head injured patients (n = 19) and tumour patients (n = 13) clear inverse relationships of ICP vs compliance exist. SAH patients (n = 5) appear to exhibit a biphasic relationship between ICP and compliance, however greater numbers of patients need to be recruited to this group. Patients with hydrocephalus (n = 34) show an initial decrease in compliance while ICP is less than 20 mmHg, thereafter compliance does not show a dependence upon ICP. A power analysis confirmed that sufficient numbers of patients have been recruited in the hydrocephalus group and a ROC analysis determined that a mean compliance value of 0.809 (lower and upper 95% CL = 0.725 & 0.894 resp.) was a critical threshold for raised ICP greater than 10 mmHg. Preliminary time-series analyses of the ICP and compliance data is revealing evidence that the cumulative time compliance is in a low compliance state (< 0.5 ml/mmHg), as a proportion of total monitoring time, increases more rapidly than the cumulative time ICP is greater than 25 mmHg. Before trials testing compliance thresholds can be designed, we need to consider not just the absolute threshold, but the duration of time spent below threshold. A survey may be required to identify a consensus of what is the minimum duration of raised ICP above 25 mmHg needed to instigate treatment.

Automation↗

PubMed2002

Sternal osteomyelitis caused by Aspergillus fumigatus in a patient with previously treated Hodgkin's disease.

This report details the case of a 67 year old woman with sternal osteomyelitis caused by Aspergillus fumigatus. She was diagnosed with Hodgkin's disease in 1975 and was successfully treated with chemotherapy. A lobectomy for recurrence localised to the left lung was complicated nine years later by severe bronchiectasis, for which she required a total left sided pneumonectomy. At surgery, a non-invasive aspergillus was found. She presented eight years later with symptoms that were initially attributed to recurrence of Hodgkins's disease, but on investigation were found to be caused by fungal sternal osteomyelitis. Treatment with itraconazole suspension at a dose of 400 mg daily was successful.

Aged↗

PubMed2001

Auto-catalyzed poly(ortho ester) microspheres: a study of their erosion and drug release mechanism.

A study has been carried out to investigate the degradation and protein release mechanisms of BSA-loaded microspheres made with auto-catalyzed poly(ortho esters) (POEs) of varying diol composition and molecular weights. Due to the instability of the POE/dichloromethane primary emulsion, microspheres made using the W/O/W double emulsion solvent extraction/evaporation method showed a multivesicular internal structure. An O/W single emulsion process yielded dense POE microspheres. Using electron scanning microscopy, the microspheres were observed to erode throughout their matrices with increasing internal pore sizes and a steady loss of mass. However, despite a substantial weight loss of almost 80% after an in vitro period of 129 days, the molecular weight of the polymer remained relatively unchanged with loss averaging about 18 and 32% for low- and high-molecular-weight POEs, respectively. Such constancy in molecular weight was similarly reflected in the glass transition temperature of the degrading microspheres. The differences in both the molecular weight loss and polydispersity index changes depended largely on the molecular weight of the polymer. For protein release of POE microspheres, an induction period followed by BSA release for a period of 3 to 10 days was observed. The lag time depended on the hydrophilicity and the molecular weight of the polymer as well as the morphology of the microspheres. Protein release was incomplete, possibly due to the slow degradation of the POE polymers, protein aggregation and protein degradation.

Acetates↗

PubMed2001

POE-PEG-POE triblock copolymeric microspheres containing protein. I. Preparation and characterization.

Poly(ortho ester) (POE)-poly (ethylene glycol) (PEG) triblock copolymers (POE-PEG-POE) with different PEG contents were synthesised as carriers for controlled protein delivery. POE-PEG-POE microspheres containing bovine serum albumin (BSA) were prepared using a double-emulsion (water-in-oil-in-water) process. In this first paper of a two-part series, we report the fundamentals of the fabrication and characterization of POE-PEG-POE microspheres. Because the triblock copolymer is more hydrophilic than neat poly(ortho ester), the triblock copolymer yields a more stable first emulsion (water-in-oil) and a greater BSA encapsulation efficiency (90% vs. 30%). No BSA is found on POE-PEG-POE microsphere surfaces measured by X-ray photoelectron spectroscopy, while uniform BSA distributions are observed within the microspheres by confocal microscopy. SEM pictures show that an increase in PEG content results in microspheres with a denser cross-section because of a more stable first emulsion and better affinity between the copolymer and water. POE-PEG(20%)-POE suffers significant swelling during the fabrication process and yields the biggest microspheres. However, the POE-PEG(30%)-POE microspheres are much smaller since the dissolution loss of POE-PEG(30%)-POE in the external water phase may be much higher than that of POE-PEG(20%)-POE. The salt concentration in the external water phase significantly affects the morphology of the resultant microspheres. Microspheres with a dense wall are produced when using pure water as the external water phase. Polymer concentration has less impact on BSA encapsulation efficiency but has a considerable effect on microsphere size and morphology. Increasing the concentration of the polyvinyl alcohol emulsifier does not cause an obvious decrease in microsphere size. However, increased BSA loading results in bigger microspheres.

Algorithms↗

PubMed2001

POE-PEG-POE triblock copolymeric microspheres containing protein. II. Polymer erosion and protein release mechanism.

The first paper of this series presented the fabrication and characterization of POE-PEG-POE triblock copolymeric microspheres containing protein. In this paper, we focus on the polymer erosion and the mechanism of protein release. Fourteen-week in vitro behaviors of POE-PEG-POE microspheres loaded with bovine serum albumin (BSA) have been monitored. SEM micrographs reveal that after 14-week incubation in PBS buffer, pH 7.4, 37 degrees C, the polymeric particles remain spherical despite mass loss of almost 90%. On the other hand, molecular weight undergoes a high initial loss of 38% and 44% during the first 2-week incubation for POE-PEG(5%)-POE and POE-PEG(10%)-POE, respectively. Then, it keeps relatively unchanged over 12 weeks. However, POE-PEG(20%)-POE copolymer provides a better compatibility between the POE and PEG blocks. Hydrolysis is homogeneous through the polymer backbone. Thus, its molecular weight remains relatively constant and mass loss shows quite sustained over the 14-week in vitro release. The similar phenomena are observed in the polydispersity index of the degrading copolymers. SDS-PAGE of the encapsulated BSA within the POE-PEG(5%)-POE microspheres displays that the structural integrity of BSA is intact for at least 8 weeks due to a mild environment provided by the copolymer. In addition, XPS and FTIR are utilized to investigate protein behaviors in the degrading microspheres. Protein release from the POE-PEG-POE microspheres shows a biphasic pattern, characterized by an initial stage followed by a non-detectable release. The non-release phase is dominated by either slow polymer degradation or dense microsphere matrix structures. The microsphere formulation is optimized and a sustained protein release over 2 weeks is achieved by using POE-PEG(20%)-POE at a high protein loading.

Animals↗

PubMed2001

Low-binding alleles of Fcgamma receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in Hispanic patients.

OBJECTIVE: To examine the relationship between allelic polymorphisms of IgG receptors (FcgammaR) and the development of lupus nephritis in a prospective study, and to determine the distribution of FcgammaR haplotypes (FcgammaRIIA and FcgammaRIIIA genotypes) in lupus patients and disease-free control subjects. METHODS: We studied 67 Hispanic systemic lupus erythematosus (SLE) patients from a prospective study of outcome and 53 disease-free control subjects. Patients were followed up longitudinally for 3 years. FcgammaRIIA and FcgammaRIIIA genotypes were determined using allele-specific polymerase chain reaction. RESULTS: Nephritis was present in 28% of patients at entry into the study and in 69% at the end of 3 years. In the nephritis group (n = 46), as well as the entire SLE cohort, there was a predominance of genotypes with low-binding alleles (FcgammaRIIa-R131 and FcgammaRIIIa-F176) at both loci (SLE nephritis patients 89% versus controls 62%; P < 0.002; odds ratio 0.20 [95% confidence interval 0.05-0.6] for risk of nephritis in individuals homozygous for either FcgammaRIIa-H131 or FcgammaRIIIaV176). The frequency of individuals homozygous for high-binding alleles at either locus decreased as the burden of disease increased (P < 0.002, by Mann-Whitney test). There was no linkage disequilibrium between FcgammaRIIA and FcgammaRIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation of the FcgammaRIIa-R131;FcgammaRIIIa-F176 haplotype (SLE patients 48% versus controls 30%) and a decrease in the frequency of the high-binding haplotype (4% versus 23%) (P < 0.002). CONCLUSION: We observed an increase in the frequency of low-binding FcgammaR alleles in an SLE population with a high prevalence of renal disease. The apparent selection for the FcgammaRIIa-R131;FcgammaRIIIa-F176 haplotype in Hispanic patients suggests that low-binding alleles of both FcgammaRIIa and FcgammaRIIIa confer risk for SLE and may act additively in the pathogenesis of disease, whereas the high-binding haplotype FcgammaRIIa-H131;FcgammaRIIIa-V176 is protective, particularly in the homozygous state.

Alleles↗

PubMed2001

Investigating Murray's law in the chick embryo.

According to the optimization principle known as Murray's law, the blood vessel geometry at a bifurcation satisfies the relation alpha = (D3(1) + D3(2))/D3(0) = 1, where D0, D1, and D2 are the diameters of the parent and two daughter vessels, respectively. Previous investigations have shown that mature blood vessels adhere to this law fairly closely. The purpose of this study was to test Murray's law in the developing extraembryonic blood vessels of 2-4 day-old chick embryos. Vessel diameters were measured manually using image analysis software. The measurements for the group of all vessels at all studied stages (n = 449) gave alpha = 1.01+/-0.34 (mean +/- SD), and the value of alpha is similar at all stages. These results indicate that Murray's law holds in the chick embryo, even before medial smooth muscle becomes functional, suggesting that blood vessels follow the same basic morphogenetic rules throughout life.

Animals↗

PubMed2001

Circumdatin G, a new alkaloid from the fungus Aspergillus ochraceus.

The crude extract of the broth of Aspergillus ochraceus was found to inhibit the final stage of polyprotein processing during hepatitis C virus replication. Bioassay-guided fractionation led to the isolation of the known compound mellein as the active component of the extract. Also isolated were circumdatin F and a new alkaloid, circumdatin G. The structure of circumdatin G was determined by spectroscopic analysis.

Alkaloids↗

PubMed2001

Necrotizing enterocolitis in the full-term neonate.

Necrotizing enterocolitis (NEC) is a relatively common disorder of multifactorial aetiology that primarily affects preterm newborns, but has been reported to occur in the full-term neonate as well. This review focuses on known and recent developments in the epidemiology, pathogenesis, diagnosis, management and prevention of NEC in the full-term neonate.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed2001

The maximal Hughes procedure.

PURPOSE: To describe the use of oblique medial and lateral periosteal flaps with the Hughes tarsoconjunctival flap for the repair of maximal defects of the lower eyelid. METHODS: A small prospective case series of eight patients requiring lower eyelid reconstruction following with maximal defect of the lower eyelid. The patients underwent a Hughes tarsoconjunctival advancement combined with oblique medial and lateral periosteal flaps, and were assessed for aesthetic outcome and surgical complications. RESULTS: All patients had uncomplicated surgery. Outcomes assessed included corneal protection, eye closure, lower eyelid retraction, complications, and patient satisfaction. Eyelid contour and protection was excellent in all patients. Postoperatively, one patient had mild lower eyelid retraction, and in a second patient, medial ectropion with mild lower eyelid retraction developed that required subsequent revision. CONCLUSIONS: The maximal Hughes procedure is a safe and effective procedure that may be performed with patients under local anesthesia and may avoid the need for more extensive techniques for surgical repair of maximal defects of the lower eyelid.

Adult↗

PubMed2001

Primate mammary gland insulin-like growth factor system: cellular localization and regulation by sex steroids.

BACKGROUND: Insulin-like growth factor 1 (IGF1) plays a critical role in estrogen-induced uterine proliferation, but it is unclear whether this estromedin function occurs in other estrogen-sensitive tissues such as the mammary gland. To elucidate this possibility, we investigated the cellular localization and hormonal regulation of mRNAs for IGF1 and 2, their cognate receptors (IGF1R, IGF2R), and IGF binding proteins 2-5 (BPs 2-5) in the rhesus monkey mammary gland. METHODS: Ovariectomized monkeys were treated with placebo, estradiol (E2), and E2 plus progesterone (E2/P4) for 3 days, after which mammary tissue was harvested for in situ hybridization and immunohistochemical analyses. RESULTS: IGF1 and IGF2 mRNA levels were significantly increased and BP2 mRNA decreased by E2 and by E2/P4 treatment. IGF1R mRNA was increased by combined E2/P treatment but not by E2 alone. BP5 mRNA was decreased by E2/P4. No differences in IGF2R, BP3, and BP4 mRNA levels were detected in any treatment group. Mammary IGF1 and IGF2 mRNA levels were both positively correlated with local epithelial proliferation, assessed by immunodetection of the proliferation-specific antigen, Ki67.IGF1 and IGF1R expression were negatively correlated with local programmed cell death, as assessed by the in situ TUNEL method. In contrast, BP2 expression was negatively correlated with epithelial proliferation and positively correlated with programmed cell death. IGF2R, BP3, BP4, and BP5 levels were not significantly correlated with either proliferation or death. CONCLUSIONS: Thus, E2-induced proliferation is associated with upregulation of both IGF1 and IGF2 expression and downregulation of BP2 expression. These data suggest that the local mammary IGF system is involved in sex steroid-induced mammary epithelial cell hyperplasia.

Animals↗

PubMed2000

Interacting fidelity defects in the replicative DNA polymerase of bacteriophage RB69.

The DNA polymerases (gp43s) of the related bacteriophages T4 and RB69 are B family (polymerase alpha class) enzymes that determine the fidelity of phage DNA replication. A T4 whose gene 43 has been mutationally inactivated can be replicated by a cognate RB69 gp43 encoded by a recombinant plasmid in T4-infected Escherichia coli. We used this phage-plasmid complementation assay to obtain rapid and sensitive measurements of the mutational specificities of mutator derivatives of the RB69 enzyme. RB69 gp43s lacking proofreading function (Exo(-) enzymes) and/or substituted with alanine, serine, or threonine at the conserved polymerase function residue Tyr(567) (Pol(Y567(A/S/T)) enzymes) were examined for their effects on the reversion of specific mutations in the T4 rII gene and on forward mutation in the T4 rI gene. The results reveal that Tyr(567) is a key determinant of the fidelity of base selection and that the Pol and Exo functions are strongly coupled in this B family enzyme. In vitro assays show that the Pol(Y567A) Exo(-) enzyme generates mispairs more frequently but extends them less efficiently than does a Pol(+) Exo(-) enzyme. Other replicative DNA polymerases may control fidelity by strategies similar to those used by RB69 gp43.

Alanine↗

PubMed2000

Cocaine use during pregnancy and intrauterine growth retardation: new insights based on maternal hair tests.

Prenatal cocaine use is more accurately measured by maternal hair assay than by urine toxicology screening or self-report. To investigate the consequences of improved measurement, the authors ascertained cocaine use during pregnancy by maternal hair test, urine test, and self-report in a sample of 691 patients recruited from one New York City hospital in 1990-1992. Associations with intrauterine growth retardation, head circumference, and length of gestation were investigated. A positive hair test at delivery was not more strongly associated with birth weight (-38.1 g; 95% CI: -164, 88.3) or head circumference (-1.73 mm; 95% CI: -5.91, 2.44) than a positive urine test at delivery (-182 g (95% CI: -295, -69.8) and -6.11 mm (95% CI: -9.99, -2.24), respectively). Cocaine concentration in hair (which was higher if urine tests were positive) had a dose-response relationship with birth weight: a 27-g decrease (95% CI: -51.9, -1.04) with each log-unit increase in concentration. Birth weights were similar among infants of never users and infants of users who stopped using cocaine before delivery. Heavier use of cocaine, but not lighter use, was associated with intrauterine growth retardation, and exposure in late pregnancy was necessary to the association. Although maternal hair tests were instrumental in clarifying these relations, their clinical use is probably not warranted.

Adult↗

PubMed2000

The transmembrane protein semaphorin 6A repels embryonic sympathetic axons.

Semaphorin 6A (Sema6A) (previously named Semaphorin VIa) is the originally described member of the vertebrate semaphorin class 6, a group of transmembrane semaphorins homologous to the insect semaphorin class 1. Although Sema-1a (previously named semaphorin I) has been implicated in axon guidance in insects, the function of Sema6A is currently unknown. We have expressed the extracellular domain of Sema6A in mammalian cells as either a monomeric or a dimeric fusion protein and tested for potential axon guidance effects on two populations of embryonic neurons in growth cone collapse and collagen matrix chemorepulsion assays. Sema6A was observed to induce growth cone collapse of sympathetic neurons with an EC50 of approximately 200 pM, although a 10-fold higher (EC50 of approximately 2 nM) concentration was necessary to induce growth cone collapse of dorsal root ganglion neurons. The activity of Sema6A is likely to depend on protein dimerization or oligomerization. Although Sema6A mRNA is expressed in complex patterns during embryonic development, it is strikingly absent from sympathetic ganglia. Sema6A is, however, expressed in areas avoided by sympathetic axons and in areas innervated by sympathetics, but before their arrival. Our results demonstrate that transmembrane semaphorins, like the secreted ones, can act as repulsive axon guidance cues. Our findings are consistent with a role for Sema6A in channeling sympathetic axons into the sympathetic chains and controlling the temporal sequence of sympathetic target innervation.

Animals↗

PubMed2000

Cellular transport processes of aminoguanidine, a nitric oxide synthase inhibitor, in the opossum kidney cell culture line.

Aminoguanidine has potential pharmacologic utility for diabetes and nitric oxide - mediated inflammation. Because aminoguanidine is positively charged at physiologic pH (pK(a) approximately 10), it is unlikely that simple diffusion is a predominant mechanism for cellular penetration. This study sought to determine the transport processes by which aminoguanidine, a cationic compound, traverses across cellular membranes. In cultured opossum kidney (OK) cell monolayers, aminoguanidine transport involved both saturable and non-saturable diffusion processes. At passage numbers below 67, the observed V(max) and K(m) for saturable influx were significantly lower than that observed at passages greater than 79 (V(max): low passage, 21.2+/-7.8 pmol/(min*mg protein), n=3; versus high passage, 129.7+/-24.3 pmol/(min*mg protein), n=3, P<0.05; K(m): low passage, 23.7+/-10.8 microM, n=3; versus high passage, 101.7+/-5.6 microM, n=3, P<0.05; mean+/-S.E.M.). Nonsaturable processes were not statistically different (k(ns): low passage, 1.6+/-0.1 pmol/(min*mg protein*microM), n=3; high passage, 1.1+/-0.2 pmol/(min*mg protein*microM) n=3). Saturable influx was temperature dependent, and independent of ATP energy, sodium gradients or changes in membrane potential. Other organic cations competitively inhibited and trans-stimulated saturable influx. Aminoguanidine influx was increased in the presence of an outwardly-directed proton gradient and was inhibited in the presence of an inwardly-directed proton gradient. Correspondingly, aminoguanidine efflux was trans79) express a saturable, bi-directional carrier-mediated process to transport aminoguanidine across cellular membranes.

Animals↗

PubMed2000

Multi-centre assessment of the Spiegelberg compliance monitor: preliminary results.

Acute brain injury states (e.g. head injury, subarachnoid haemorrhage) show clear inverse relationships of ICP vs compliance, with ICP instability at times of lower compliance states. Variance in compliance values is large in hydrocephalus where ICP is relatively lower and compliance higher. Nonetheless, early experience shows that compliance data influence decisions on CSF diversion treatments. Future work will focus on the ability of intracranial compliance to predict ensuing ICP instability and methodological refinement for monitoring patients who have higher compliance states.

Brain↗