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Biomedical subjects

W K Chan

Publications and source records attributed to W K Chan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Phase II trial of systemic recombinant interleukin-2 in the treatment of refractory nasopharyngeal carcinoma.

BACKGROUND: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. METHODS: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5-6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-alpha, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. RESULTS: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3x) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. CONCLUSION: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.

Adult↗
PubMed2001

Therapeutic use of Bausch & Lomb PureVision contact lenses.

PURPOSE: To evaluate the Bausch & Lomb PureVision contact lens as a continuous wear contact lens for therapeutic indications in a prospective open-ended non-randomized clinical trial. METHODS: Patients with a variety of corneal and ocular surface disease conditions presenting at the Singapore National Eye Centre who required therapeutic continuous contact lens wear were enrolled. Therapeutic indications included pain relief, corneal protection, and enhancement of corneal wound healing. Success or failure of specific treatment indications was assessed in all cases, with evaluation of lens performance and fit characteristics, and the presence of ocular complications or lens-related complications was noted. RESULTS: There were 54 patients (54 eyes), and the mean duration of continuous contact lens wear was 1.1 months. Conditions treated included post-surgical indications (n = 36) (post-keratoplasty or ocular surface transplantation, post-LASIK or PRK surgery) bullous keratopathy (n = 7), chemical burns (n = 3), epithelial abrasions or recurrent corneal erosion syndromes (n = 3), corneal perforations (n = 3), neurotrophic ulcer (n = 1), and corneal laceration (n = 1). For the indication of corneal healing (40 eyes), improved healing was noted in 38 eyes (96%), with full healing occurring in 33 eyes (83%). For pain relief (28 eyes), 27 patients (96%) had considerable or complete pain relief, and the remaining patient reported partial pain relief. For corneal protection (21 eyes), lens wear was fully protective in all cases. The lens performance and fitting characteristics surpassed any previous therapeutic lenses used by the investigators. Complications related to contact lens wear were limited to one case of a culture-negative corneal infiltrate requiring cessation of therapeutic lens wear and one case of a loosely fit lens. CONCLUSIONS: Our results show that the PureVision contact lens exhibits good safety and efficacy when utilized as a continuous wear therapeutic lens. With the theoretical advantage of increased oxygen transmissibility reducing the risk of hypoxia-related complications, this new lens may be one step closer to the ideal therapeutic contact lens. The PureVision contact lens is now our primary bandage lens of choice in our corneal, external disease, and refractive surgery services.

Adolescent↗
PubMed2000

Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4.

Resveratrol, a phytoalexin found in red wine, has been shown to possess antioxidant and antimutagenic properties. Incubation of resveratrol with Sf9 insect microsomes containing baculovirus-derived human cytochrome P450 3A4 (CYP3A4) and NADPH-cytochrome P450 reductase showed that resveratrol inactivated CYP3A4 in a time- and NADPH-dependent manner. Resveratrol, erythromycin and troleandomycin inactivated CYP3A4 at a similar rate (as reflected by k(inact)) whereas the binding affinity to CYP3A4 (as reflected by K(I)) was in the order of: troleandomycin > erythromycin > resveratrol. (K(I) and k(inact) for CYP3A4 inactivation by resveratrol, erythromycin and troleandomycin are 20 microM and 0.20 min(-1), 5.3 microM and 0.12 min(-1) and 0.18 microM and 0.15 min(-1), respectively.) Fractionation studies of red wine showed that fractions that did not contain resveratrol inactivated CYP3A4 significantly. In addition, the resveratrol content in red wine used in the study was too low to account for the degree of CYP3A4 inactivation observed after red wine treatment. Inactivation studies using a variety of red wine types showed that the CYP3A4 inactivation did not correlate to their resveratrol content. In summary, data here showed that resveratrol is an effective mechanism-based inactivator of CYP3A4; however, it is not one of the main red wine constituents that are responsible for CYP3A4 inactivation by red wine. Nevertheless, inactivation of CYP3A4 by resveratrol may cause clinically relevant drug interactions with CYP3A4 substrates.

Animals↗
PubMed2000

Developmental expression of a novel Ftz-F1 homologue, ff1b (NR5A4), in the zebrafish Danio rerio.

The Ftz-F1 genes encode orphan receptors of the nuclear receptor superfamily. The mammalian Ftz-F1 homologue, SF-1, has been found to be essential for the proper development of the adrenal-gonadal axis and it also plays a critical role in mammalian sex-determination. We report here the isolation and characterisation of a novel zebrafish Ftz-F1 gene, ff1b. Whole-mount in situ hybridization revealed onset of expression in the developing rostral diencephalon at 22 h post-fertilization (h.p.f.). Later, at 30 h.p.f., transcripts could be detected in the anterior regions of the pancreatic anlagen. Expression in both locations peaks at 36 h.p.f. and disappears at around 48 h.p.f.

Amino Acid Sequence↗
PubMed2000

Temporal expression and T3 induction of thyroid hormone receptors alpha1 and beta1 during early embryonic and larval development in zebrafish, Danio rerio.

The effects of thyroid hormones on metabolism and development are mediated by thyroid hormone receptors (TRs). We report the cloning and characterization of a TR beta1 cDNA from zebrafish. Southern blot analysis revealed that there is a single genomic locus for the TR beta gene, while the TR alpha gene potentially has two loci. Multiple TR alpha and TR beta transcripts were detected in adult tissues. Using a semiquantitative RT-PCR assay, zygotic expression of TR alpha1 and TR beta1 were shown to occur before the midblastula transition stage. In transiently transfected HeLa cells, TR alpha1 displayed constitutive transactivation in the absence of ligands, which was slightly enhanced by triiodothyronine (T3). The transactivating activity of TR beta1 was strictly ligand-dependent and repressed in the absence of T3. Finally, the T3 induction of TR alpha1 and TR beta1 mRNAs was demonstrated in zebrafish embryos and larvae. The auto-induction of TR alpha1 and TR beta1 may serve a regulatory role during the embryonic and larval development of zebrafish.

Amino Acid Sequence↗
PubMed2000

Phospho-dependent association of neurofilament proteins with kinesin in situ.

Recent studies demonstrate co-localization of kinesin with neurofilament (NF) subunits in culture and suggest that kinesin participates in NF subunit distribution. We sought to determine whether kinesin was also associated with NF subunits in situ. Axonal transport of NF subunits in mouse optic nerve was perturbed by the microtubule (MT)-depolymerizing drug vinblastine, indicating that NF transport was dependent upon MT dynamics. Kinesin co-precipitated during immunoprecipitation of NF subunits from optic nerve. The association of NFs and kinesin was regulated by NF phosphorylation, since (1) NF subunits bearing developmentally delayed phospho-epitopes did not co-purify in a microtubule motor preparation from CNS while less phosphorylated forms did; (2) subunits bearing these phospho-epitopes were selectively not co-precipitated with kinesin; and (3) phosphorylation under cell-free conditions diminished the association of NF subunits with kinesin. The nature and extent of this association was further examined by intravitreal injection of (35)S-methionine and monitoring NF subunit transport along optic axons. As previously described by several laboratories, the wave of NF subunits underwent a progressive broadening during continued transport. The front, but not the trail, of this broadening wave of NF subunits was co-precipitated with kinesin, indicating that (1) the fastest-moving NFs were associated with kinesin, and (2) that dissociation from kinesin may foster trailing of NF subunits during continued transport. These data suggest that kinesin participates in NF axonal transport either by directly translocating NFs and/or by linking NFs to transporting MTs. Both Triton-soluble as well as cytoskeleton-associated NF subunits were co-precipitated with kinesin; these data are considered in terms of the form(s) in which NF subunits undergo axonal transport.

Animals↗
PubMed2000

The flow patterns within the impeller passages of a centrifugal blood pump model.

The effects of impeller geometry on the performance of a centrifugal blood pump model [the MSCBP design of Akamatsu and Tsukiya (The Seventh Asian Congress of Fluid Mechanics (1997), 7-10) at a 1:1 scale] have been investigated both experimentally and computationally. Four impeller designs were tested for pump hydraulic performance at the operating point (i.e. 2000 rpm), using blood analog as the working fluid. Each impeller has seven blades with different configurations including the radial straight blade and backward swept blade designs. The results show that both designs can achieve a stable head of about 100 mm Hg at the operating point. Subsequent investigations involved the visualization of the relative flow field within the impeller passages via the image de-rotation system coupled with a 2.5 W argon ion laser. Flow structures in all sectors of each impeller were examined and discussed. To further quantify the possible effects of blade geometry to thrombus formation and hemolysis, computational fluid dynamics (CFD) was used to simulate a simplified two-dimensional blade-to-blade flow analysis so as to estimate the shear stress levels. The results indicate that the stress levels found within the blade passages are generally below the threshold level of 150 N/m(2) for extensive erythrocyte damage to occur. There are some localized regions near the leading edge of the blades where the stress levels are 60% above the threshold level. However, given such a short residence time for the fluid particles to go through these high shear stress regions, their effects appear to be insignificant.

Blood Flow Velocity↗
PubMed2000

Analytical investigation of leakage flow in disk clearance of a magnetically suspended centrifugal impeller.

Leakage flow through the disk clearance of a magnetically suspended centrifugal blood pump is essential for a good washout. An analytical approach, based on the theory of lubrication, is used to predict the leakage volume flow rate, nondimensional radial velocity, nondimensional mean pressure distribution, and comparative shear stress distribution for different disk clearance geometry under varying rotational speeds. The results showed that nondimensional mean pressure distribution and nondimensional radial velocity distribution along the clearance are independent of rotational speed. The flow through the gap depends on a nondimensional parameter S that denotes the ratio of centrifugal forces to the head generating capability of the impeller. It was found that an impeller having a lower S has less possibility of flow reversals in the gap, and gap with maximum height at the outside radius also is more susceptible to flow reversals at the impeller surface. The comparative shear stress within the gap reveals that, in general, the scalar stress is below 500 N/m2.

Algorithms↗
PubMed2000

Is automatic mode switching effective for atrial arrhythmias occurring at different rates? A study of the efficacy of automatic mode and rate switching to simulated atrial arrhythmias by chest wall stimulation.

Automatic mode switching (AMS) is a useful means to avoid rapid ventricular response during atrial fibrillation (AF), but AMS cannot occur if the detected atrial rate during AF is below the mode switching criteria. This may be the result of antiarrhythmic medications, or when the atrial events fall within the atrial blanking period, or if the atrial amplitudes during AF are too small to be sensed. We hypothesize that the addition of an automatic rate switching (ARS) algorithm may complement AMS response during AF with different detected atrial rates. We studied the Marathon DDDR pacemaker (Model 294-09, Intermedics Inc.) with the AMS and ARS algorithms that are independently programmable but can also operate in combination. AF sensed above the AMS rate (160 beats/min) will lead to VDIR pacing, whereas AF below AMS rate will be tracked at an interim rate as dictate by the ARS, at a ventricular response that is 20 beats/min above the sensor indicated rate. Atrial tachyarrhythmias were simulated by chest wall stimulation (CWS). CWS was applied to 33 patients (16 men, 17 women, mean age 69 +/- 11 years) with a Marathon DDDR pacemaker using an external pacer to simulate AF occurring at two rate levels: above the AMS rate (programmed at 160 beats/min) at 180 beats/min and below the AMS rate at 120 beats/min. The maximum, minimum, and mean ventricular rates during CWS in DDDR mode with AMS alone, ARS alone, and their combination were compared. During CWS at 120 beats/min, the AMS plus ARS setting showed a mean ventricular rate of 79 +/- 3 beats/min and 124 +/- 14 beats/min in the AMS setting alone (P < 0.01). With CWS at 180 beats/min, the mean ventricular rate in the AMS plus ARS setting compared to the AMS setting alone was not significantly different. However, the variation in ventricular pacing rate was 7 +/- 14 beats/min in the AMS plus ARS setting and 40 +/- 42 beats/min in the AMS setting (P < 0.05). In conclusion, AMS is effective for simulated atrial tachyarrhythmias sensed above the AMS rate. Combined AMS with ARS is useful to handle simulated atrial tachyarrhythmia at a slower rate and to avoid rate fluctuation during AMS. There is also a possibility that this can be applied to the naturally occurring atrial tachyarrhythmias.

Aged↗
PubMed2000

Haemophagocytic syndrome and histiocytic necrotising lymphadenitis (Kikuchi's disease).

A young boy presented with a rash, fever, and cervical lymphadenopathy, originally thought to be caused by tuberculosis. A lymph node biopsy showed the features of Kikuchi's disease, with necrosis and histiocytic infiltration without neutrophils. No evidence of tuberculosis was found on staining, culture, or the polymerase chain reaction. Bone marrow biopsy revealed prominent haemophagocytosis, and a diagnosis of haemophagocytic syndrome was reached. The aetiology of haemophagocytic syndrome, and its association with Kikuchi's lymphadenitis, is discussed.

Bone Marrow↗
PubMed2000

Inverse design and CFD investigation of blood pump impeller.

In this paper, a three-dimensional inverse design method using mean swirl specification is applied to the design of centrifugal blood pump impeller blades. CFD investigation of the passage flows is carried out to analyze the flow field and pressure generated across the blade. The results show that the possibility of blood cells' damage may not be increased when the pressure developed is increased. This technique can provide designers valuable insight on the development of efficient blood pump with reduced risk of blood traumatization.

Computer Simulation↗
PubMed2000

Experimental and computational studies of the relative flow field in a centrifugal blood pump.

The relative flow field within the impeller passage of a centrifugal blood pump had been examined using flow visualization technique and computational fluid dynamics. It was found that for a seven-blade radial impeller design, the required flow rate and static pressure rise across the pump could be achieved but the flow field within the blades was highly undesirable. Two vortices were observed near the suction side and these could lead to thrombus formation. Preliminary results presented in this article are part of our overall effort to minimize undesirable flow patterns such flow separation and high shear stress regions within the centrifugal blood pump. This will facilitate the future progress in developing a long-term clinically effective blood pump.

Computer Simulation↗
PubMed1999

Cross-talk between the aryl hydrocarbon receptor and hypoxia inducible factor signaling pathways. Demonstration of competition and compensation.

The aryl hydrocarbon receptor (AHR) and the alpha-class hypoxia inducible factors (HIF1alpha, HIF2alpha, and HIF3alpha) are basic helix-loop-helix PAS (bHLH-PAS) proteins that heterodimerize with ARNT. In response to 2,3,7,8-tetrachlorodibenzo-p-dioxin, the AHR. ARNT complex binds to "dioxin responsive enhancers" (DREs) and activates genes involved in the metabolism of xenobiotics, e.g. cytochrome P4501A1 (Cyp1a1). The HIF1alpha.ARNT complex binds to "hypoxia responsive enhancers" and activates the transcription of genes that regulate adaptation to low oxygen, e.g. erythropoietin (Epo). We postulated that activation of one pathway would inhibit the other due to competition for ARNT or other limiting cellular factors. Using pathway specific reporters in transient transfection assays, we observed that DRE driven transcription was markedly inhibited by hypoxia and that hypoxia responsive enhancer driven transcription was inhibited by AHR agonists. When we attempted to support this cross-talk model using endogenous loci, we observed that activation of the hypoxia pathway inhibited Cyp1a1 up-regulation, but that activation of the AHR actually enhanced the induction of Epo by hypoxia. To explain this unexpected additivity, we examined the Epo gene and found that its promoter harbors DREs immediately upstream of its transcriptional start site. These experiments outline conditions where inhibitory and additive cross-talk occur between the hypoxia and dioxin signal transduction pathways and identify Epo as an AHR-regulated gene.

Base Sequence↗
PubMed1999

The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study.

Grapefruit juice is an inhibitor of cytochrome P-450 3A4 (CYP3A4). This study was designed to assess the in vitro and in vivo effects of grapefruit juice on sertraline metabolism. The in vitro assay involved analysis of sertraline metabolism by CYP3A4 using CYP3A4-expressed human beta-lymphoblast microsomes. The in vivo study involved high-performance liquid chromatographic analysis of serum trough levels of sertraline and desmethylsertraline in 5 patients who had been taking their usual dose of sertraline for > or =6 weeks, followed by concurrent use of sertraline with grapefruit juice for 1 week. The in vitro assay demonstrated that grapefruit juice inhibited the formation of desmethylsertraline in a dose-dependent manner. In the in vivo study, mean serum sertraline levels were determined in 5 patients with a history of depression (4 males and 1 female). The mean age of the patients was 68.6 years, their mean weight was 69.6 kg, and their mean sertraline dosage was 55 mg/d. The results of the in vivo study appeared to be consistent with the in vitro findings, in that mean (+/- SD) serum sertraline trough levels increased significantly from 13.7+/-4.9 microg/L before to 20.2+/-4.4 microg/L (P = 0.047) after administration of grapefruit juice. Thus the in vitro study demonstrated that grapefruit juice can inhibit the metabolism of sertraline. A larger study is warranted to substantiate the clinical significance of the in vivo findings.

Administration, Oral↗
PubMed1999

HPV testing in primary screening of older women.

Certain types of the human papilloma virus (HPV) are well established as the primary cause of cervical cancer. Several studies have shown that HPV testing can improve the detection rate of high-grade cervical intraepithelial neoplasia (CIN), but these have been carried out primarily in younger women. In this study we evaluated the role of HPV testing as an adjunct to cytology in women aged 35 or over. An additional aim was to evaluate commercially available kits for HPV testing. A total of 2988 eligible women aged 34 or more attending for a routine smear in 40 general practitioner practices received HPV testing in addition to routine cytology, after having given written informed consent. Samples were assayed by polymerase chain reaction (PCR) and two versions of the Hybrid Capture test for HPV, and women were invited for colposcopy if there was any cytological abnormality (including borderline smears) or the PCR test was positive. Any apparent abnormality was biopsied and loop-excision was performed as necessary. CIN was judged by histology; 42 women had high-grade CIN, of which six were cytology negative (86% sensitivity for borderline or worse) and three had a borderline smear (79% sensitivity for mild dyskaryosis or worse). The positive predictive value of a borderline smear was only 3.1%. Eleven high-grade lesions were negative by the PCR HPV test (sensitivity 74%). The first generation Hybrid Capture II test had a similar sensitivity but an unacceptably high false positive rate (18.3%), while the newer Hybrid Capture II microtitre kit had a 95% sensitivity and a 2.3% positivity rate in normal women when used at a 2 pg ml(-1) cut-off (positive predictive value 27%). Cytology performed very well in this older cohort of women. The newer Hybrid Capture II microtitre test may be a useful adjunct, especially if the results reported here are reproducible in other studies. A combined screening test offers the possibility of greater protection and/or longer screening intervals, which could reduce the overall cost of the screening programme.

Adenocarcinoma↗