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Biomedical subjects

W L Chan

Publications and source records attributed to W L Chan.

At least 19 recordsLinked to original sources
PubMed2002

Autotuning positive feedback time delay controller for dead time processes.

Biased relay feedback tests are applied to dead time processes to obtain their ultimate gains and ultimate frequencies. First-order process with dead time models are then fitted to the estimated gains and frequencies. A time delay controller that incorporates a simple compensator with a delay element in positive feedback can be derived from the fitted model. The time delay controller gives better performance comparing with classical Ziegler and Nichols tuned PID controller. Experimental study is included to demonstrate the effectiveness of the proposed tuning scheme and the time delay control algorithm.

Computer Simulation↗
PubMed2001

Leukocyte mitochondria depolarization and apoptosis in advanced heart failure: clinical correlations and effect of therapy.

OBJECTIVES: The purpose of this study was to examine the changes in leukocyte mitochondrial transmembrane potential (MTP) and its association with apoptosis in congestive heart failure (CHF). BACKGROUND: Congestive heart failure is a heterogeneous syndrome with multiple hemodynamic, neuroendocrine and immune abnormalities. Although edematous CHF may be associated with endotoxemia and increased cytokine production, peripheral blood leukocyte functions in advanced CHF remain unclear. METHODS: Thirty patients with acute decompensated CHF (mean age [+/- SEM] 74.9 +/- 3.1 years) and 20 healthy controls underwent determination of MTP, intracellular oxidants and apoptosis in three subsets of peripheral blood leukocytes. The measurements were repeated after the time of recompensation. RESULTS: Patients with acute CHF showed marked MTP reduction and increased intracellular oxidant formation in three subsets of leukocytes upon entry into the study. These changes were more prominent in patients with peripheral edema. The decline in MTP was correlated with the severity of the peripheral edema and plasma concentration of cortisol, nitrogen metabolites and tumor necrosis factor-alpha (p < 0.01). After clinical stabilization, MTP gradually recovered. Leukocytes underwent increased propensity of apoptosis one week after the time of recompensation. CONCLUSIONS: The mitochondrial depolarization and apoptosis of leukocytes in decompensated heart failure suggest that CHF is associated with severity-dependent impairments in leukocyte function. Accentuated hormonal and cytokine abnormalities and increased circulating oxidants may contribute to these changes. Early and aggressive management of advanced heart failure is helpful in the recovery of these immune abnormalities.

Aged↗
PubMed2001

Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes.

CD4(+) (Th) and CD8(+) (Tc) T and NK lymphocytes can be divided into type 1 and 2 subsets according to their cytokine secretion profile. Studies on the role of lymphocyte subsets in human diseases have been hampered by the lack of stable surface markers to define them. Recently, we reported that ST2L and IL-18R are stably expressed on murine Th2 and Th1 cells, respectively. In this study, we generated Abs to human homologues of ST2L and IL-18R and tested them against Th1/Th2, Tc1/Tc2, and NK1/NK2 lines and PBMCs from healthy individuals. We show for the first time that ST2L and IL-18R are stable selective cell surface markers for human Th2/Tc2/NK2 and Th1/Tc1/NK1 lymphocytes, respectively. We then investigated PBMCs from HIV-infected patients and HIV-negative individuals, to test whether Abs to these two surface markers could be used directly to monitor lymphocyte subset distribution in human diseases. We found a clear Th1 to Th2 shift in the HIV-infected individuals, thus settling a long-standing controversy and include, for the first time, Tc and NK cells as well. Therefore, these cell surface molecules could serve as important determinants of the immune status of human diseases in general, and thereby could be useful for therapeutic monitoring and intervention.

Biomarkers↗
PubMed2001

Enhancement of the anti-herpetic effect of trichosanthin by acyclovir and interferon.

Trichosanthin (TCS) is a type I ribosome-inactivating protein that has a wide range of pharmacological activities. The present study investigated the effectiveness of TCS on herpes simplex virus (HSV-1). The anti-viral activity and toxicity of TCS on Vero cells were measured. Results showed that the ED(50), TD(50) and the therapeutic indices were 38.5, 416.5 and 10.9 microg/ml, respectively. Anti-viral activity of TCS was substantially potentiated when it was used in conjunction with other anti-viral agents. The ED(50) of TCS was reduced 125-fold by acyclovir at a concentration of 0.001 microg/ml, which was practically devoid of significant anti-viral activity. Similarly, the ED(50) of TCS was reduced 100-fold by interferon-alpha2a at a concentration of 100 IU/ml. In conclusion, TCS is effective against HSV-1 and other anti-viral agents such as acyclovir or interferon can potentiate its action substantially.

Acyclovir↗
PubMed2001

Regulation of ST2L expression on T helper (Th) type 2 cells.

T1/ST2L, an IL-1 receptor homologue, is selectively expressed on murine Th2 cells and specific anti-ST2L antibodies can profoundly modulate the Th1/Th2 balance in vivo. Naive CD4+ T cells do not express ST2L but do so on activation with specific antigen in the presence of IL-4 or when stimulated with low doses of antigen in the absence of exogenously added IL-4. Similarly enhanced ST2L expression occurred after stimulation of Th2 cells with antigen or the mitogen ConA in the presence of APC. Restimulation of Th2 cells in the presence of IFN-gamma led to a decreased expression of ST2L to below basal levels. Conversely, Th2 cells cultured with IL-4 led to increased ST2L expression. The reduced expression of ST2L in response to high doses of antigen is also reversed by the neutralization of IFN-gamma. Using an ST2L promoter/luciferase reporter gene construct, we show that the distal but not proximal ST2L promoter is responsible for specific gene expression in Th2 cells. IL-4 enhances, whereas IFN-gamma suppresses ST2L expression via direct modulation of the distal promoter of the ST2L gene. These data provide a mechanistic explanation for the selective expression of ST2L on Th2 cells.

Animals↗
PubMed2001

Coincidence detection FDG PET in the management of oncological patients: attenuation correction versus non-attenuation correction.

The aim of this study was to determine if attenuation correction (AC) in a dual-head, coincidence, positron emission tomography imaging system (Co-PET) improved image quality, lesion detection, patient staging and management of various malignant neoplasms, compared to non-attenuation corrected (NAC) images. Thirty patients with known or suspected malignant neoplasms underwent fluorodeoxyglucose (FDG) Co-PET, which was correlated with histopathology, computed tomography (CT) and other conventional imaging modalities and clinical follow-up. The number and location of FDG avid lesions detected on the AC images and NAC Co-PET images were blindly assessed by two independent observers. Semi-quantitative grading of image clarity and lesion-to-background quality was performed. This revealed markedly improved image clarity and lesion-to-background quality in the AC versus NAC Co-PET images. AC Co-PET was statistically superior to NAC Co-PET in relation to lesion detection (P<0.01) and tumour staging (P<0.01). NAC Co-PET demonstrated 51 of the 65 lesions (78%) detected by AC Co-PET. AC Co-PET altered tumour staging in five additional patients (16%) compared to NAC Co-PET. Management was altered in two of these five patients.

Adult↗
PubMed2001

Integrin mobilizes intracellular Ca(2+) in renal vascular smooth muscle cells.

Peptides with the Arg-Gly-Asp (RGD) motif induce vasoconstriction in rat afferent arterioles by increasing the intracellular Ca(2+) concentration ([Ca(2+)](i)) in vascular smooth muscle cells (VSMC). This finding suggests that occupancy of integrins on the plasma membrane of VSMC might affect vascular tone. The purpose of this study was to determine whether occupancy of integrins by exogenous RGD peptides initiates intracellular Ca(2+) signaling in cultured renal VSMC. When smooth muscle cells were exposed to 0.1 mM hexapeptide GRGDSP, [Ca(2+)](i) rapidly increased from 91 +/- 4 to 287 +/- 37 nM and then returned to the baseline within 20 s (P < 0.05, 34 cells/5 coverslips). In controls, the hexapeptide GRGESP did not trigger Ca(2+) mobilization. Local application of the GRGDSP induced a regional increase of cytoplasmic [Ca(2+)](i), which propagated as Ca(2+) waves traveling across the cell and induced a rapid elevation of nuclear [Ca(2+)](i). Spontaneous recurrence of smaller-amplitude Ca(2+) waves were found in 20% of cells examined after the initial response to RGD-containing peptides. Blocking dihydropyridine-sensitive Ca(2+) channels with nifedipine or removal of extracellular Ca(2+) did not inhibit the RGD-induced Ca(2+) mobilization. However, pretreatment of 20 microM ryanodine completely eliminated the RGD-induced Ca(2+) mobilization. Anti-beta(1) and anti-beta(3)-integrin antibodies with functional blocking capability simulate the effects of GRGDSP in [Ca(2+)](i). Incubation with anti-beta(1)- or beta(3)-integrin antibodies inhibited the increase in [Ca(2+)](i) induced by GRGDSP. We conclude that exogenous RGD-containing peptides induce release of Ca(2+) from ryanodine-sensitive Ca(2+) stores in renal VSMC via integrins, which can trigger cytoplasmic Ca(2+) waves propagating throughout the cell.

Animals↗
PubMed2000

Trichosanthin interacts with and enters cells via LDL receptor family members.

The type-I ribosome-inactivating protein trichosanthin displays selective cytotoxicity, suggesting specific mechanisms for entry into cells. Here we show that trichosanthin binds specifically to the endocytic receptors LRP and megalin, and that binding as well as uptake into cells is inhibited by the receptor-associated protein (RAP). The results suggest that the known abortifacient and renotoxic actions of trichosanthin are caused by LRP-mediated uptake in trophoblasts and megalin-mediated uptake in proximal tubule epithelial cells, respectively.

Endocytosis↗
PubMed2000

Engineering of a mini-trichosanthin that has lower antigenicity by deleting its C-terminal amino acid residues.

Trichosanthin is a ribosome-inactivating protein that possesses antitumor and antiviral activities. Clinical trials of trichosanthin on AIDS patients, however, elicit anaphylactic reactions. To reduce the antigenicity of trichosanthin as a drug while preserving its biological activity, the C-terminal domain (residues 203 to 247), which contains a putative antigenic site, was systemically deleted. We have found that the minimum length of trichosanthin that can fold into an active conformation is residue 1 to 240. The mini-trichosanthin (C7) generated by deleting the last seven C-terminal amino acid residues has 2.7-fold decrease in antigenicity, 10-fold reduction in in vitro ribosome-inactivation activity, and in vivo cytotoxicity toward K562 cells, and 2-fold reduction in abortificient activity. Structural analyses of C7 indicate decrease in the helix content, increased exposure of Trp192, and lower thermodynamic stability. The deletion of the C-terminal residues (Leu241 to Ala247) probably perturbs local structure of the C-terminal antigenic epitope that results in the decrease in antigenicity and activities of C7.

Abortifacient Agents, Nonsteroidal↗
PubMed2000

Planar versus SPET imaging in the assessment of condylar growth.

The aim of this study was to compare two methods of quantifying 99Tc(m)-methylene diphosphonate uptake in the mandibular condyle. The study groups consisted of 23 patients with mandibular asymmetry and 16 normal volunteers aged 10-30 years. The accuracy and reproducibility of SPET using condyle-to-clivus ratios was compared with planar analysis using condyle-to-L4 (fourth lumbar vertebra) ratios. Quantitative analysis was correlated with semi-quantitative grading by three observers. Normal ranges for condyle-to-L4 and condyle-to-clivus ratios in individuals aged 11 years or over were determined. These ratios are useful in the serial monitoring of patients with condylar hyperplasia to establish when condylar growth has ceased and hence the type of surgery performed. Visual interpretation of condylar activity should use a combination of planar and SPET images and be performed in conjunction with quantitative analysis. Semi-quantitative grading on SPET images detected more subtle differences in condylar activity than planar images (using quantitative analysis as a standard).

Adolescent↗
PubMed2000

Magnolol attenuates peroxidative damage and improves survival of rats with sepsis.

Reactive oxygen species and peroxidative damage are implicated in the pathophysiology of sepsis. Magnolol is a compound extracted from the Chinese medicinal herb Magnolia officinalis and has multiple pharmacological effects, notably antioxidant functions. To determine whether magnolol can modulate the course of sepsis, survival rate and biochemical parameters were analyzed in rats with sepsis with various treatment protocols. Magnolol at doses ranging from 10(-9) g/kg to 10(-5) g/kg was administered either before or after induction of sepsis by cecal ligation and puncture. Magnolol did not modulate the course of sepsis induced by two cecal punctures. When one cecal puncture was performed, a moderately evolving type of sepsis was induced, and the survival rate of affected rats was significantly improved by pretreatment with 10(-7) g/kg magnolol. The beneficial effect was partially retained if magnolol was administered 6 hours after onset of sepsis when a higher dose (10(-5) g/kg) was used. The intensity of lipid peroxidation in plasma, liver, and lung of septic rats was also attenuated in a treatment-dependent manner. Magnolol at this dose range exerted these beneficial effects probably through its antioxidant efficacy. These significant results may suggest magnolol as a candidate agent for the treatment of sepsis.

Animals↗
PubMed2000

Mechanical strain memory in airway smooth muscle.

We investigated the effect of a single rapid stretch on poststretch force and myosin phosphorylation in bovine tracheal smooth muscle. When unstimulated muscle strips were stretched from suboptimal length to optimal length (L(o)), poststretch steady-state force was not significantly different from that of unstretched control at L(o). However, when carbachol-activated muscle strips were stretched from suboptimal length to L(o), poststretch force and myosin phosphorylation were lower than control and significantly correlated with initial length. When poststretch muscle strips were allowed to relax for 1 h and then activated by K(+) depolarization, the developed force remained significantly correlated with initial length. When the same strain was applied in 23 increments to minimize peak stress, poststretch force and myosin phosphorylation increased significantly, approaching the levels expected at L(o). Furthermore, poststretch force development increased after each cycle of contraction and relaxation, approaching the control level after four cycles. These results suggest that activated airway smooth muscle cells can retain relatively precise memory of past strain when they are stretched rapidly with high stress.

Animals↗
PubMed1999

Lowering of trichosanthin immunogenicity by site-specific coupling to dextran.

Trichosanthin is a type I ribosome-inactivating protein possessing a broad spectrum of biological and pharmacological activities. Therapeutic use of this compound is hampered by its immunogenicity. It was shown earlier that coupling of dextran to trichosanthin can increase plasma half-life and reduce antigenicity. However, the site where dextran attaches to trichosanthin cannot be controlled; ideally, it should be at or near the antigenic determinant. The present study attempted to couple dextran to trichosanthin at a potential antigenic site. By site-directed mutagenesis, two sites, R29 and K173, were replaced by cysteine, and dextran was coupled to the newly created cysteine residues. The dextran-trichosanthin complex retained 50% of abortifacient activity and had a mean residence time in rats 27-fold longer than natural trichosanthin. Acute hypersensitivity reaction in guinea pigs was reduced greatly after coupling of K173C (a trichosanthin mutant with lysine-173 replaced by cysteine) to dextran. Compared with natural trichosanthin, dextran-K173C had a decrease in IgG and IgE response, whereas the coupling of R29C (a trichosanthin mutant with arginine-29 replaced by cysteine) to dextran did not show significant reduction of immunogenicity. This suggests that K173 but not R29 is located at or near an antigenic determinant. This study has demonstrated an alternative approach for mapping of antigenic determinants. The information obtained is also useful in producing an improved trichosanthin derivative for therapeutic use.

Acute-Phase Reaction↗
PubMed1999

Results of coronary stenting after delayed angioplasty of the culprit vessel in patients with recent myocardial infarction.

Little information is available concerning the effect of late coronary stenting in patients with recent myocardial infarction, especially long-term results. We retrospectively reviewed our results of 57 stent placements in 52 consecutive patients who received stents at an infarct-related lesion 24 hr to 30 days after an acute myocardial infarctions (median, 14 days). The average age was 67 years; 90% were male. Two patients who suffered from acute stent thrombosis received revascularization again and two early deaths were due to refractory cardiogenic shock before discharge. Mean patient clinical follow-up was 18.3 +/- 6.5 months. There were 1 subacute stent thrombosis, 1 cardiogenic death, and 10 patients (20.8%) in total suffering from angina class II to IV. Angiographic follow-up was performed in 36 patients (80%) at a mean of 7.5 +/- 3.1 months. Of these 36 patients, only 1 (3% of the total population undergoing follow-up angiography) had reocclusion at follow-up, but restenosis existed in 18 patients (50%). We conclude that there is still relatively high incidence of angiographic recurrence that is often silent in long-term follow-up, though the long-term result of late stenting in recent MI is low incidence of reocclusion.

Aged↗
PubMed1999

Immune effector mechanism in parasitic infections.

In this article is a summary of our recent findings on the role of nitric oxide (NO) as an effector mechanism against the intracellular parasite, Leishmania major. NO is produced in large amounts in murine macrophages following activation by IFNgamma synthesized by Th1 cells. NO production is inhibited by IL-4, a product of Th2 cells. A set of stable cell surface markers has now been identified. ST2L and IL-18R are selectively expressed on Th2 and Th1 cells respectively. Antibody against ST2L can down-regulate Th2 cells in the highly susceptible BALB/c mice leading to control of otherwise fatal L. major infection. These results show directly the critical role of the balance between Th1 and Th2 cells in cutaneous leishmaniasis.

Animals↗
PubMed1999

Retropharyngeal abscess on a Ga-67 scan: a case report.

A retropharyngeal abscess is a potentially fatal deep neck infection. Classical symptoms include fever, neck swelling, sore throat, dysphagia, and cervical rigidity. Sometimes small children present with nonspecific symptoms. We report a rare case whereby the Ga-67 citrate scan was the first investigation to reveal an inflammatory process in the retropharyngeal or submastoid region of a 3-year-old child with sepsis. This directed the line of investigation to a more precise anatomic imaging modality, CT scanning, to localize the abscess. With prompt administration of intravenous antibiotics, the child recovered quickly and did not require surgery. The Ga-67 scan is thus a useful screening test to detect inflammatory foci because of its high sensitivity. It is also valuable in the follow-up of the patient's response to therapy.

Anti-Bacterial Agents↗
PubMed1999

A proinflammatory role for IL-18 in rheumatoid arthritis.

IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA.

Animals↗