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Biomedical subjects

H P Ng

Publications and source records attributed to H P Ng.

At least 19 recordsLinked to original sources
PubMed2006

Induction of autoimmune thyroiditis and hypothyroidism by immunization of immunoactive T cell epitope of thyroid peroxidase.

Autoimmune thyroiditis (AT) is characterized by a continuous inflammatory self-destructive process that eventually leads to chronic progressive dysfunction of the thyroid. In a previously established experimental AT model, C57bl/6 mice immunized with recombinant mouse thyroid peroxidase (TPO) (rmTPO) developed lymphocytic thyroiditis and anti-TPO antibody but not chronic hypothyroidism. To determine the immunodominant epitope(s) of TPO, T cell proliferation assays were performed in which rmTPO-primed lymph nodes cells were reacted with recombinant mTPO fragments or short overlapping synthetic TPO peptides. Within residue 405-849, peptide 540-559 gave the maximum proliferation response with a stimulation index more than 12. Mice immunized with peptide 540-559 developed antibody against rmTPO and native mouse TPO protein, lymphocytic thyroiditis, and hypothyroidism. In conclusion, this study demonstrated that TPO is the autoantigen for the development of lymphocyte thyroiditis and thyroid dysfunction, and peptide 540-559 is the immunodominant T cell epitope of TPO. Identification of T cell epitopes of TPO may enable the development of immunotherapy to prevent chronic hypothyroidism in AT.

Amino Acid Sequence↗
PubMed2004

In vitro effects of local anaesthetics on the thromboelastographic profile of parturients.

BACKGROUND: Post-dural puncture headache can be an incapacitating complication of obstetric epidural analgesia/anaesthesia and early or prophylactic epidural blood patch (EBP) is one of the treatment options. Although local anaesthetic (LA) agents have been shown to have anticoagulation effects in vitro, peri-partum women are known to be hypercoagulable. We postulated that the presence of residual LA might not result in impaired haemostasis of the EBP in parturients. METHODS: Blood samples from 10 healthy term parturients were subjected to thromboelastography after the addition of four different LA (lidocaine, bupivacaine, levobupivacaine, and ropivacaine) preparations. RESULTS: There was a significant reduction in reaction (R) and coagulation (K) time (P<0.001, P<0.05) and an increase in alpha degrees angle (P<0.01) when comparing undiluted blood with the saline control group. Maximum amplitude (MA) and clot lysis (Ly30) did not change significantly despite the 50% dilution. The thromboelastographic parameters of all four LA-treated groups were no different from their saline controls and from each other. CONCLUSION: At clinical dosages, LA did not cause any hypocoagulable changes on the thromboelastographic profile of healthy parturients.

Amides↗
PubMed2004

Neonatal post-intubation subglottic stenosis.

Acquired subglottic stenosis is a compication or neonatal endotracheal intubation. Although it is rare, it contributes significantly to the morbidity and physical well being of post extubated neonates. A 20-day old neonate, ventilated for meconium aspiration syndrome and persistent fetal circulation, presented with marked stridor and respiratory embarrassment. A stenosed subglottic area was found on rigid bronchoscopy. Anterior cricoid split was performed to relieve the obstruction. He is asymptomatic post operatively.

Cricoid Cartilage↗
PubMed2003

Development of a murine model of autoimmune thyroiditis induced with homologous mouse thyroid peroxidase.

Autoimmune thyroid disease (AITD) is a common autoimmune disease. Thyroid peroxidase (TPO) is a well characterized autoantigen in AITD. Autoantibodies and autoreactive T lymphocytes to TPO are believed to play a major role in the pathogenesis of lymphocytic thyroiditis. To understand the pathogenic mechanisms of AITD and the role of TPO, we have established a mouse model of lymphocytic thyroiditis by immunizing C57Bl/6 (H-2(b)), CBA (H-2(k)), and C57Bl/6 x CBA F1 mice with recombinant murine TPO (rmTPO) ectodomain comprising amino acid residue 1-837 produced in Escherichia coli. Mice were immunized with 30 microg purified ectodomain in complete Freund's adjuvant. Antibodies against rmTPO were detected in the serum of all mice from day 21 onward. Draining lymph node cells from rmTPO-immunized animals showed dose-dependent proliferation to TPO stimulation. Mice killed at d 50 and 90 revealed variable degrees of thyroiditis with infiltration of mononuclear cells and destruction of thyroid follicles. C57Bl/6 and the F1 mice, in comparison with CBA mice, showed a greater degree of thyroiditis. There was a lack of correction between the intensity of thyroiditis and the anti-TPO response. Immunotyping of the thyroid cellular infiltrates showed predominantly CD4+ T cells and B220+ B cells but scanty CD8+ T cells. None of the control mice injected with the purified fusion partner developed anti-TPO antibodies and thyroiditis. In conclusion, a genuine autoimmune mouse model of lymphocytic thyroiditis was established using autologous mouse TPO. This new model induced with autologous TPO will lead to a better understanding of the mechanisms in destructive thyroiditis and will assist in the development of new strategies for modulating the pathogenic immune response.

Animals↗
PubMed2002

The effects of hypertonic saline solution (7.5%) on coagulation and fibrinolysis: an in vitro assessment using thromboelastography.

We studied the effects of hypertonic (7.5%) and normal saline on coagulation and fibrinolysis in an in vitro model using thromboelastography of human whole blood. Reaction times increased and alpha angles decreased with hypertonic saline replacement at 7.5% blood volume compared with similar dilution with normal saline. At 10% blood volume replacement with hypertonic saline, reaction and coagulation times were significantly increased and alpha angles were decreased. Clot lysis at 30 min was also significantly reduced. We conclude that 7.5% hypertonic saline solution has anticoagulant effects if it replaces 7.5% or more of blood volume.

Adult↗
PubMed2001

CCR1-specific non-peptide antagonist: efficacy in a rabbit allograft rejection model.

The classic signs of acute cellular rejection during organ transplantation include the infiltration of mononuclear cells into the interstitium. This recruitment of leukocytes into the transplanted tissue is promoted by chemokines like RANTES. Since RANTES is a potent agonist for the CC chemokine receptor CCR1, we examined whether the CCR1 antagonist BX 471 was efficacious in a rabbit kidney transplant rejection model. BX 471 was able to compete with high affinity with the CCR1 ligands MIP-1alpha and RANTES for binding to HEK 293 cells expressing rabbit CCR1. BX 471 was a competitive antagonist of rabbit CCR1 in Ca(2+) flux studies. Two separate studies in which animals were subcutaneously implanted with slow release pellets of BX 471 demonstrated that animals implanted with BX 471 had increased survival compared with untreated controls or animals implanted with placebo. The mean survival time for the placebo group was 12.33+/-1.7 days. The animals in the BX 471 treated group had mean survival times of 16.9+/-2.1 and 16.0+/-1.7 days, respectively, for the two studies. Analysis of the combined data by Student t-test gave a P value of 0.03 that is significant at the 0.05 level. In addition, there was a marked reduction in the urea and creatinine levels in the BX 471 treated animals compared with the control and placebo groups in both studies. Finally, pathologic analysis of the kidneys in the rabbit renal transplantation model from animals in the different groups showed that BX 471 was similar to cyclosporin in its ability to prevent extensive infarction of transplanted kidneys. Based on the data from these studies, BX 471 shows clear efficacy at the single dose tested compared with animals treated with placebo.

Animals↗
PubMed2001

Intraoperative single-shot "3-in-1" femoral nerve block with ropivacaine 0.25%, ropivacaine 0.5% or bupivacaine 0.25% provides comparable 48-hr analgesia after unilateral total knee replacement.

PURPOSE: To compare analgesia after intraoperative single shot "3-in-1" femoral nerve block (FNB) in combination with general anesthesia using ropivacaine 0.25%, ropivacaine 0.5% with bupivacaine 0.25% for total knee replacement (TKR). METHODS: We performed a randomized, double-blind study in 48 patients for elective TKR under general anesthesia. Patients were randomized to one of four groups (C: sham block, R1: "3-in-1" FNB using 30 mL of ropivacaine 0.25%, R2: "3-in-1" FNB using 30 mL of ropivacaine 0.5%, B: "3-in-1" FNB using 30 mL of bupivacaine 0.25%). Verbal pain score (VPS) both at rest and movement were assessed for 48 hr after TKR (0=none; 1=mild; 2=moderate; 3=severe). Total morphine consumption and its associated side effects, duration of hospitalization after operation were also compared. RESULTS: There were no differences in patients' physical characteristics, intraoperative morphine usage, operation time, tourniquet time or length of hospitalization between the four groups. When compared with group C, the VPS was significantly lower in groups R1, R2 and B at one, four, eight, 24 and 48 hr after TKR (P <0.05). The morphine requirement of groups R1, R2 and B were also significantly lower when comparing with group C up to 48 hr postoperatively (P <0.05). There were no significant differences in VPS and postoperative morphine requirement at any time between groups R1, R2 and B. CONCLUSION: "3-in-1" FNB with ropivacaine provided analgesia that was clinically comparable to that of bupivacaine up to 48 hr after TKR. Increasing the concentration of ropivacaine from 0.25% to 0.5% failed to improve the postoperative analgesia of "3-in-1" FNB.

Adult↗
PubMed2001

Effect of ondansetron pretreatment on pain after rocuronium and propofol injection: a randomised, double-blind controlled comparison with lidocaine.

In a randomised, controlled, double-blinded trial to study the effect of ondansetron pretreatment on the pain produced after intravenous injection of rocuronium and propofol in comparison with lidocaine, 60 patients were randomly assigned to one of three groups. Group 1 received 5 ml of intravenous 0.9% sodium chloride solution pretreatment, group 2 received ondansetron 4 mg (2 mg.ml-1 solution) diluted into a 5-ml solution, and group 3 received 50 mg lidocaine (5 ml 1% solution); this was followed 1 min later by rocuronium and propofol. Pain was reduced significantly in the ondansetron and lidocaine groups (p < 0.0001) compared with placebo, and significantly better with lidocaine than with ondansetron (p = 0.02). We conclude that ondansetron is effective in relieving the pain of rocuronium but is not as effective as lidocaine.

Adult↗
PubMed2000

A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection.

Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.

Animals↗
PubMed2000

Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1.

The CC chemokine receptor-1 (CCR1) is a prime therapeutic target for treating autoimmune diseases. Through high capacity screening followed by chemical optimization, we identified a novel non-peptide CCR1 antagonist, R-N-[5-chloro-2-[2-[4-[(4-fluorophenyl)methyl]-2-methyl-1-piperazinyl ]-2-oxoethoxy]phenyl]urea hydrochloric acid salt (BX 471). Competition binding studies revealed that BX 471 was able to displace the CCR1 ligands macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES, and monocyte chemotactic protein-3 (MCP-3) with high affinity (K(i) ranged from 1 nm to 5.5 nm). BX 471 was a potent functional antagonist based on its ability to inhibit a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression, and leukocyte migration. BX 471 demonstrated a greater than 10,000-fold selectivity for CCR1 compared with 28 G-protein-coupled receptors. Pharmacokinetic studies demonstrated that BX 471 was orally active with a bioavailability of 60% in dogs. Furthermore, BX 471 effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis. This study is the first to demonstrate that a non-peptide chemokine receptor antagonist is efficacious in an animal model of an autoimmune disease. In summary, we have identified a potent, selective, and orally available CCR1 antagonist that may be useful in the treatment of chronic inflammatory diseases.

Administration, Oral↗
PubMed2000

Species selectivity of a small molecule antagonist for the CCR1 chemokine receptor.

The species specificity of a small molecule antagonist for the human CCR1 chemokine receptor, 2-2-diphenyl-5-(4-chlorophenyl)piperidin-1-yl)valeronitrile (CCR1 antagonist 1), has been examined using cloned CCR1 receptors from various species. The compound was able to bind to rabbit, marmoset, and human CCR1, and was able to block the functional activation of these receptors. However, it failed to significantly displace radiolabeled macrophage inflammatory protein-1alpha (MIP-1alpha) binding to mouse CCR1 at concentrations up to 10 microM. These data suggested that the antagonist binding site is well-conserved in rabbit, marmoset and human CCR1, but not in mouse CCR1. The functional selectivity and mechanism of action for CCR1 antagonist 1 were further characterized. CCR1 antagonist 1 blocked the increase in intracellular Ca(2+) stimulated by CCR1 agonists, but had no effect on N-formyl-Met-Leu-Phe (FMLP), monocyte chemotactic protein-1 (MCP-1) and stromal-derived factor 1alpha (SDF1alpha)-induced Ca(2+) mobilization, demonstrating functional selectivity for CCR1. Since CCR1 antagonist 1 is a functional antagonist of marmoset and rabbit CCR1 receptors, it should be possible to test its efficacy in animal models of disease.

Amino Acid Sequence↗
PubMed2000

Chemokine receptor antagonists.

Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. Chemokines appear to be involved in a variety of proinflammatory and autoimmune diseases and this makes them and their receptors very attractive therapeutic targets. This review highlights current efforts toward obtaining highly specific chemokine receptor antagonists and discusses their chemistry and potential role as disease modifiers.

Arteriosclerosis↗
PubMed2000

Effect of remifentanil compared with fentanyl on intraocular pressure after succinylcholine and tracheal intubation.

Rapid sequence induction using succinylcholine is associated with an increase in intraocular pressure (IOP). This may lead to loss of ocular contents in open globe injuries. No method has previously been shown to prevent this increase in IOP. We investigated whether remifentanil, an ultra-short-acting opioid, could attenuate this increase in IOP during rapid sequence induction of anaesthesia. Forty-five patients were randomized blindly to receive remifentanil 1 microgram kg-1, fentanyl 2 micrograms kg-1 or placebo 1 min before thiopental, succinylcholine and tracheal intubation. IOP and haemodynamic variables were measured before, 1 min after the test solution, 30 s after thiopental, 30 s after succinylcholine, immediately after intubation and then every 3 min for 9 min. Remifentanil obtunded the increase in IOP after succinylcholine and intubation, so it could be suitable for use in open globe injuries.

Adult↗
PubMed2000

Pattern of congenital heart disease and access to tertiary cardiac care in Malaysia.

This prospective, descriptive study was carried out to determine the pattern and the type of congenital heart disease seen in the Paediatric Departments in 4 government hospitals. The accessibility of surgical or transcatheter interventional treatment was also assessed. Consecutive new patients seen for suspected congenital heart disease from 1/1/95 till 31/12/95 (Group I) were registered. Records of patients seen from 1/1/95 to 31/8/95 (Group Ia) were reviewed 6 months after presentation to determine the nature of treatment received. Group II were cardiac patients who were first seen prior to the year 1995 and had undergone cardiac surgery or transcatheter interventional procedures in 1995. Of the 375 patients registered in the 4 hospitals, 250 were new patients and 125 were patients first seen prior to 1995 and had surgery or transcatheter interventional procedures in 1995. Of the 250 new patients, 83.2% had acyanotic cardiac lesions and 16.8% had cyanotic lesions. Ventricular septal defect was the commonest lesion, constituting 37.2%, followed by patent arterial duct (18.8%) and atrial septal defects (9.6%). At 6 month review, access to close-heart surgery or transcatheter interventional treatment were readily available. However, for patients with ventricular septal defects, 42.1% who required closure were still waiting for surgery 6 months after presentation. Of the 4 patients with Fallot's Tetralogy who required surgery, 2 had modified Blalock-Taussig shunt and 2 were awaiting surgery. In 1995, a total of 204 cardiac procedures were performed, there were 114 (55.9%) open heart procedures, 50 (24.5%) surgical ligation of the arterial duct, 28 (13.7%) modified Blalock-Taussig shunts, 11 (5.4%) transcatheter duct occlusion and 1 (0.5%) balloon valvuloplasty. The mean age of Fallot's Tetralogy repair was 6.4 years. No corrective surgery was performed for patients with complex cardiac lesions from the 4 hospitals in 1995. In conclusion, the pattern of congenital heart disease was similar to that seen world wide. Except for patent arterial duct, access to surgical treatment was inadequate.

Health Services Accessibility↗
PubMed1999

Discovery of novel non-peptide CCR1 receptor antagonists.

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.

Anti-Inflammatory Agents↗
PubMed1999

Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.

Amidines↗
PubMed1999

Toxicological and antioxidant effects of short-term dehydroepiandrosterone injection in young rats fed diets deficient or adequate in vitamin E.

This study examined the in vivo antioxidant and/or prooxidant effect of short-term dehydroepiandrosterone (DHEA) injection and the effect of dietary vitamin E. Male Sprague-Dawley rats (4 wk old) were fed vitamin E-deficient or vitamin E-adequate (30 mg DL-alpha-tocopheryl acetate/kg) diet for 4 weeks followed by intraperitoneal injection of DHEA for 1 week. The results showed that DHEA injection caused a dose-dependent decrease in body weight, and this effect was more pronounced in vitamin E-deficient rats. In contrast, DHEA injection significantly increased liver, kidney and adrenal weights. Hepatic vitamin E content was significantly lowered by vitamin E deficiency, which led to significantly increased ex vivo and iron-induced lipid peroxidation. DHEA injection did not affect hepatic vitamin E content but significantly decreased ex vivo and iron-induced lipid peroxidation in vitamin E-deficient rats. Hepatic total sulfhydryl (SH) groups and non-protein SH contents were not affected by vitamin E but were significantly increased by DHEA injection, which at 100 mg/kg was not more effective than at 50 mg/kg. Hepatic glutathione S-transferase (GST) activity was significantly decreased by DHEA, but vitamin E alleviated such a decrease. DHEA injection significantly increased hepatic glucose 6-phosphate dehydrogenase (G6PD) activity, and the effect was dose dependent in vitamin E-deficient rats. Thus, DHEA may compensate for vitamin E deficiency in vivo, and this effect is masked when dietary vitamin E is adequate. The antioxidant effect of DHEA is accompanied by decreased body weights, enlarged (fat-laden) tissues and altered activities of hepatic GST and G6PD.

Analysis of Variance↗