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Biomedical subjects

K Tan

Publications and source records attributed to K Tan.

At least 19 recordsLinked to original sources
PubMed2001

Nasal and exhaled nitric oxide in response to occupational latex exposure.

BACKGROUND: Latex sensitivity is an increasing problem among health-care workers. Allergic responses are associated with changes in nitric oxide (NO) generation and the changes secondary to latex have not been described. METHODS: A total of 22 subjects comprising equal numbers of control volunteers and subjects with self-reported latex sensitivity were recruited to undergo latex skin prick testing. Symptom scores, exhaled nitric oxide (eNO), and nasal nitric oxide (nNO) were studied 1) before and after a controlled latex challenge (n=16), and 2) at the beginning and end of the working week, during exposure to latex (n=18). RESULTS: Latex challenge caused a significant fall in nNO levels in latex-sensitive subjects, compared to normal control subjects (P=0.04). eNO levels also decreased in the latex-sensitive subjects after latex challenge, but to a lesser degree. There were no significant differences between the beginning and end of the working week in terms of eNO or nNO in either group, although symptom scores showed a nonsignificant increase in latex-sensitive subjects. CONCLUSION: Fall in nasal NO after latex challenge is associated with reported symptomatic latex sensitivity, and this corresponds to latex skin prick test positivity. Neither nNO nor eNO showed a clear relationship to routine workplace exposure.

Adult↗
PubMed2001

A comparative genomics approach to prediction of new members of regulons.

Identifying the complete transcriptional regulatory network for an organism is a major challenge. For each regulatory protein, we want to know all the genes it regulates, that is, its regulon. Examples of known binding sites can be used to estimate the binding specificity of the protein and to predict other binding sites. However, binding site predictions can be unreliable because determining the true specificity of the protein is difficult because of the considerable variability of binding sites. Because regulatory systems tend to be conserved through evolution, we can use comparisons between species to increase the reliability of binding site predictions. In this article, an approach is presented to evaluate the computational predictions of regulatory sites. We combine the prediction of transcription units having orthologous genes with the prediction of transcription factor binding sites based on probabilistic models. We augment the sets of genes in Escherichia coli that are expected to be regulated by two transcription factors, the cAMP receptor protein and the fumarate and nitrate reduction regulatory protein, through a comparison with the Haemophilus influenzae genome. At the same time, we learned more about the regulatory networks of H. influenzae, a species with much less experimental knowledge than E. coli. By studying orthologous genes subject to regulation by the same transcription factor, we also gained understanding of the evolution of the entire regulatory systems.

Amino Acid Sequence↗
PubMed2000

The role of alpha and beta chains in ligand recognition by beta 7 integrins.

Integrins alpha(E)beta(7) and alpha(4)beta(7) are involved in localization of leukocytes at mucosal sites. Although both alpha(E)beta(7) and alpha(4)beta(7) utilize the beta(7) chain, they have distinct binding specificities for E-cadherin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), respectively. We found that mutation of the metal ion-dependent adhesion site (MIDAS) in the alpha(E) A-domain (D190A) abolished E-cadherin binding, as did mutation F298A on the A-domain surface near the MIDAS cleft. A docking model of the A-domain with E-cadherin domain 1 indicates that coordination of the alpha(E) MIDAS metal ion by E-cadherin Glu(31) and a novel projection of Phe(298) into a hydrophobic pocket on E-cadherin provide the basis for the interaction. The location of the binding site on the alpha(E) A-domain resembles that on other integrins, but its structure appears distinctive and particularly adapted to recognize the tip of E-cadherin, a unique integrin ligand. Additionally, mutation of the beta(7) MIDAS motif (D140A) abolished alpha(E)beta(7) binding to E-cadherin and alpha(4)beta(7)-mediated adhesion to MAdCAM-1, and alpha(4) chain mutations that abrogated binding of alpha(4)beta(1) to vascular cell adhesion molecule-1 and fibronectin similarly reduced alpha(4)beta(7) interaction with MAdCAM-1. Thus, although specificity can be determined by the integrin alpha or beta chain, common structural features of both subunits are required for recognition of dissimilar ligands.

Amino Acid Sequence↗
PubMed2000

Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin.

Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best characterized example of lymphocyte adhesion to a tissue-specific cell adhesion molecule, as opposed to a vascular endothelial adhesion molecule, is the interaction between integrin alpha(E)beta(7) on intraepithelial lymphocytes and E-cadherin on epithelial cells. However, the molecular basis for an integrin-cadherin interaction is not well defined. Realization that the cadherin domain adopts a topology similar to the immunoglobulin (Ig) fold suggested that integrin recognition of E-cadherin might be similar to recognition of Ig superfamily ligands. Thus, we modeled domain 1 of human E-cadherin and studied the role of solvent-exposed loops that connect Ig-like core-forming beta strands. Mutational analyses localized the integrin alpha(E)beta(7) recognition site to the top of domain 1 at the face formed by the BC and FG loops, a site distinct from the region recognized in intercellular adhesion molecule (ICAM)-1, -2, and -3, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), vascular cell adhesion molecule 1 (VCAM-1), and fibronectin by their integrin ligands. Moreover, the integrin alpha(E)beta(7) binding site is distinct from the homophilic binding site on E-cadherin. These studies provide a conceptual basis for integrin-cadherin binding and extend the model that an Ig-like fold can serve as a scaffold for recognition.

Amino Acid Sequence↗
PubMed2000

Once daily versus multiple daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require repeated courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher concentrations less often. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH STRATEGY: We searched the Cystic Fibrosis specialist trials register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search: February 2000. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy and/or toxicity, in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Both reviewers independently extracted data and assessed trial quality. Authors of one study were contacted to obtain missing information. MAIN RESULTS: Two trials reporting results from a total of 70 patients were included in this review. Both trials compared once-daily dosing with thrice-daily dosing reporting data on Forced Expiratory Volume at one second (FEV1), Forced Vital Capacity (FVC), nutritional status and side effects. There was no significant difference in efficacy or in the incidence of ototoxicity and nephrotoxicity between treatment groups. REVIEWER'S CONCLUSIONS: Despite a lack of difference between the two groups we feel that these results should be viewed with caution as the numbers of patients involved was small and lacks the power to detect a difference between the groups. This systematic review has highlighted the need for a well designed, adequately-powered, multicentre, randomised controlled trial assessing the efficacy of once-daily versus multiple-daily dosing of intravenous aminoglycosides for pulmonary exacerbations in cystic fibrosis.

Adolescent↗
PubMed2000

The current status of senior house officer postgraduate education in a single region.

OBJECTIVE: To assess postgraduate education (PGE) for paediatric senior house officers (SHOs) in a single region. METHODS: A survey of all paediatric SHOs in the region was undertaken in the form of a questionnaire and telephone contact. The standard set by the Committee of Postgraduate Medical Deans for SHO education formed the basis for the questionnaire; there should be (i) a designated educational supervisor for each SHO, (ii) regular work appraisal and counselling and (iii) 4 h protected teaching per week. Supplementary questions were asked regarding methods of teaching and study leave. RESULTS: There was a 92% response rate from SHOs and 90% of SHOs contacted had a named educational supervisor. The mean time for protected teaching per week was 2.14 h, although this varied widely between centres. There were many different teaching methods used and 82% of SHOs had no difficulty in obtaining study leave. There was a particular problem for those who were working shifts or cross-covering. CONCLUSIONS: Our study has shown that paediatric SHOs in Wales are reasonably satisfied with their postgraduate education, although there is considerable variation between different units. Several areas have been highlighted which need to be improved if we are to provide SHOs with adequate preparation for the specialist registrar training grade.

Education, Medical, Graduate↗
PubMed2000

Chemical analysis and antimicrobial studies on three species of Ferulago from Greece.

The chemical composition of the essential oils of the flowering parts and of the hexane extracts of the leaves, of three species of the genus Ferulago (Apiaceae) from Greece, i.e., F. thyrsiflora, F. sylvatica and F. nodosa, was analysed by GC and GC-MS. Manoyl oxide isomers and lupanine, were identified in the hexane extracts of F. thyrsiflora. Dillapiole, was identified in all hexane extracts. Ent-3 beta-hydroxy-13-epi-manoyl oxide was identified and isolated from the essential oil of F. thyrsiflora. All these compounds are new reports for the genus Ferulago and are useful chemotaxonomic markers. Chemical data of F. thyrsiflora is presented for the first time. The essential oils and the extracts were investigated for their antimicrobial activity against Gram-positive and Gram-negative microorganisms.

Anti-Bacterial Agents↗
PubMed2000

Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells.

Signals derived from antigen-presenting cells (APC) influence the functional differentiation of CD4(+) T cells. We report here that Serrate1 (Jagged1), a ligand for the Notch1 receptor, may contribute to the differentiation of peripheral CD4(+) T cells into either helper or regulatory cells. Our findings demonstrate that antigen presented by murine APC overexpressing human Serrate1 induces naive peripheral CD4(+) T cells to become regulatory cells. These cells can inhibit primary and secondary immune responses, and transfer antigen-specific tolerance to recipient mice. Our results show that Notch signalling may help explain 'linked' suppression in peripheral tolerance, whereby tolerance induced to one epitope encompasses all epitopes on that antigen during the course of an immune response.

Animals↗
PubMed2000

Malignant infantile osteopetrosis presenting with neonatal hypocalcaemia.

Presentation characteristics were reviewed in 14 children from 12 families with malignant infantile osteopetrosis seen at two large referral centres for bone marrow transplantation. Children from six of these families presented initially with symptoms of hypocalcaemia. These comprised early or late neonatal convulsions in six cases (corrected serum calcium < 1.5 mmol/l), and vomiting and irritability (serum calcium 1.68 mmol/l) in another. One other related child had severe and persistent jittering episodes almost certainly attributable to hypocalcaemia. In seven of eight cases, these symptoms developed during the first 14 days of life. Although occasionally reported previously, malignant infantile osteopetrosis remains essentially unrecognised as a cause of neonatal hypocalcaemia, often resulting in diagnostic confusion and delay. This is important in the context of curative haemopoietic stem cell transplantation where preservation of sight may depend on early intervention.

Biomarkers↗
PubMed2000

Immunological tolerance to inhaled antigen.

Regulatory mechanisms exist in the immune system to limit the induction of pathogenic responses to antigens encountered within the respiratory tract. The development of allergic disease is thought to arise as a result of the breakdown in these regulatory processes. In this review we examine the nature of immune responses generated to inhaled protein antigens and the mechanisms used to establish tolerance to inhaled antigens.

Antigens↗
PubMed2000

Regulation of insulin-like growth factor-binding protein-3 ternary complex in feline diabetes mellitus.

The 140 kDa ternary complex of insulin-like growth factor-binding protein-3 (IGFBP-3), IGFs and an acid-labile subunit (ALS) has previously been shown to be decreased in diabetes mellitus in humans and rats. We have studied IGF-I levels and ternary complex formation in normal and diabetic cats. Total IGF-I concentrations, measured by RIA using des(1-3)-IGF-I as tracer were (+/-s.e.m.) 54+/-13 nmol/l in eight normal and 227+/-57 nmol/l in eight diabetic cats (P<0.01). The size-distribution of IGFBPs in the cat circulation was determined by incubation with (125)I-IGF-II and Superose 12 chromatography. In normal animals 26+/-2% of the (125)I-IGF-II were in a 140 kDa form compared with 48+/-5% in diabetic cats (P<0.01). When samples from normal and diabetic animals were co-incubated 52+/-3% were at 140 kDa. A similar shift was seen when normal cat and normal human serum were co-incubated. A 2-fold increase in the 140 kDa form in diabetic cats was confirmed first by size-fractionating samples and then performing a ligand-binding assay with (125)I-IGF-I or -II and charcoal separation. SDS-PAGE and Western ligand blotting demonstrated a 45 kDa doublet (presumably IGFBP-3) and 30-35 kDa forms. There were no apparent differences between normal and diabetic profiles on SDS-PAGE, suggesting that a proportion of IGFBP-3 which circulates 'free' in normal cats forms a ternary complex in the diabetic circulation. We conclude that (i) in contrast to humans and rats, ALS is the limiting factor for ternary complex formation in normal cats, (ii) ALS concentrations increase in feline diabetes mellitus and, by promoting ternary complex formation, this leads to an increase in total IGF-I concentrations, and (iii) total IGF-I concentrations may not be reliable in the diagnosis of acromegaly in diabetic cats.

Acromegaly↗
PubMed1999

The crystal structure of a T cell receptor in complex with peptide and MHC class II.

The crystal structure of a complex involving the D10 T cell receptor (TCR), 16-residue foreign peptide antigen, and the I-Ak self major histocompatibility complex (MHC) class II molecule is reported at 3.2 angstrom resolution. The D10 TCR is oriented in an orthogonal mode relative to its peptide-MHC (pMHC) ligand, necessitated by the amino-terminal extension of peptide residues projecting from the MHC class II antigen-binding groove as part of a mini beta sheet. Consequently, the disposition of D10 complementarity-determining region loops is altered relative to that of most pMHCI-specific TCRs; the latter TCRs assume a diagonal orientation, although with substantial variability. Peptide recognition, which involves P-1 to P8 residues, is dominated by the Valpha domain, which also binds to the class II MHC beta1 helix. That docking is limited to one segment of MHC-bound peptide offers an explanation for epitope recognition and altered peptide ligand effects, suggests a structural basis for alloreactivity, and illustrates how bacterial superantigens can span the TCR-pMHCII surface.

Animals↗
PubMed1999

Crystal structure of enteropeptidase light chain complexed with an analog of the trypsinogen activation peptide.

Enteropeptidase is a membrane-bound serine protease that initiates the activation of pancreatic hydrolases by cleaving and activating trypsinogen. The enzyme is remarkably specific and cleaves after lysine residues of peptidyl substrates that resemble trypsinogen activation peptides such as Val-(Asp)4-Lys. To characterize the determinants of substrate specificity, we solved the crystal structure of the bovine enteropeptidase catalytic domain to 2.3 A resolution in complex with the inhibitor Val-(Asp)4-Lys-chloromethane. The catalytic mechanism and contacts with lysine at substrate position P1 are conserved with other trypsin-like serine proteases. However, the aspartyl residues at positions P2-P4 of the inhibitor interact with the enzyme surface mainly through salt bridges with the Nzeta atom of Lys99. Mutation of Lys99 to Ala, or acetylation with acetic anhydride, specifically prevented the cleavage of trypsinogen or Gly-(Asp)4-Lys-beta-naphthylamide and reduced the rate of inhibition by Val-(Asp)4-Lys-chloromethane 22 to 90-fold. For these reactions, Lys99 was calculated to account for 1.8 to 2.5 kcal mol(-1) of the free energy of transition state binding. Thus, a unique basic exosite on the enteropeptidase surface has evolved to facilitate the cleavage of its physiological substrate, trypsinogen.

Amino Acid Sequence↗
PubMed1999

Structure of a heterophilic adhesion complex between the human CD2 and CD58 (LFA-3) counterreceptors.

Interaction between CD2 and its counterreceptor, CD58 (LFA-3), on opposing cells optimizes immune recognition, facilitating contacts between helper T lymphocytes and antigen-presenting cells as well as between cytolytic effectors and target cells. Here, we report the crystal structure of the heterophilic adhesion complex between the amino-terminal domains of human CD2 and CD58. A strikingly asymmetric, orthogonal, face-to-face interaction involving the major beta sheets of the respective immunoglobulin-like domains with poor shape complementarity is revealed. In the virtual absence of hydrophobic forces, interdigitating charged amino acid side chains form hydrogen bonds and salt links at the interface (approximately 1200 A2), imparting a high degree of specificity albeit with low affinity (K(D) of approximately microM). These features explain CD2-CD58 dynamic binding, offering insights into interactions of related immunoglobulin superfamily receptors.

Amino Acid Sequence↗
PubMed1999

Alterations in atrial electrophysiology associated with chronic atrial fibrillation in man.

BACKGROUND: The purpose of this study was to determine the changes in atrial electrophysiology associated with chronic persistent atrial fibrillation in man. METHODS AND RESULTS: Atrial monophasic action potential duration at 90% repolarization and the effective refractory period were measured in 13 patients with chronic persistent atrial fibrillation after low-energy endocardial cardioversion, and compared to eight controls without a history of atrial fibrillation. Measurements were made at the right atrial appendage and midlateral right atrial wall at basic, 600 ms and 400 ms drive cycle lengths. In control patients, the effective refractory periods were significantly longer at the atrial appendage than the lateral wall at 600 ms (right atrial appendage 265 ms, midlateral right atrial wall 228 ms, P<0.05), and 400 ms cycle lengths (right atrial appendage 270 ms, midlateral right atrial wall 218 ms, P<0.05), but this was not evident in patients with atrial fibrillation. The monophasic action potentials and effective refractory periods at both atrial sites were shorter in the atrial fibrillation patients compared to controls; however, only the effective refractory periods at atrial appendage at 600 ms (atrial fibrillation 210 ms, controls 265 ms, P<0.001), and 400 ms cycle lengths (atrial fibrillation 200 ms, controls 270 ms, P>0.001) reached statistical significance. Effective refractory period dispersion was significantly greater in controls than in patients with atrial fibrillation (cycle length 600 ms: controls 36, atrial fibrillation 13, P=0.01; cycle length 400 ms: controls 54, atrial fibrillation 18, P<0.01). CONCLUSIONS: In patients without a history of atrial fibrillation, the refractory period at the right atrial appendage is significantly longer than at the midlateral right atrial wall. This 'normal' pattern of atrial refractory dispersion is lost in patients with chronic persistent atrial fibrillation, with marked shortening of the effective refractory period at the right atrial appendage. This may explain the high risk of recurrence of atrial fibrillation following successful electrical cardioversion.

Action Potentials↗
PubMed1999

Metastatic liposarcoma of the brain: case report and review of the literature.

A 74-year-old woman presented with an acute left hemiplegia. CT demonstrated an irregular mass in the right parietal region of the brain. Two years previously, she had undergone wide local excision of a liposarcoma from her thigh. Craniotomy was performed and the lesion removed. Subsequent histology confirmed a liposarcoma. The brain is an exceptionally rare site of first recurrence of a liposarcoma. This case report presents a pathological rarity and briefly reviews the literature relevant to clinicians.

Aged↗