Biomedical subjects

L Chung

Publications and source records attributed to L Chung.

At least 19 recordsLinked to original sources

PubMed2006

A complex fistula caused by an eroding pelvic mesh sling.

Pelvic mesh slings are increasingly used to create abdomino-pelvic partitions. This procedure is usually safe and carries low morbidity and mortality rates. However, we report a case of a 60-year-old male with a history of an abdomino-perineal resection for a low rectal carcinoma followed by adjuvant radiotherapy, who presented with an entero-vesicle-cutaneous fistula as a result of the polypropylene mesh eroding into his small bowel. He had to have a total cystectomy, small bowel resection and mesh removal in order to alleviate his symptoms.

Adenocarcinoma↗

PubMed2006

Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease.

Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are rare autoimmune diseases which share the common feature of non-inflammatory vasculopathy. Studies evaluating pregnancy outcomes in these patients have yielded conflicting results. We sought to describe the outcomes of pregnancies associated with SSc and MCTD followed at our center utilizing a retrospective review of all pregnant women with SSc and MCTD followed at Stanford University from 1993 to 2003. We identified 20 pregnancies occurring in 13 women with SSc or MCTD. Twelve pregnancies occurred in seven women with SSc and eight pregnancies occurred in six women with MCTD. The overall preterm delivery rate was 39% and small for gestational age infants occurred in 50% and 63% of pregnancies associated with SSc and MCTD, respectively. Fetal loss complicated two pregnancies in women with severe diffuse SSc and the antiphospholipid antibody syndrome. There were no cases of congenital heartblock among infants, and only one case of pre-eclampsia was observed. Maternal flares of disease during pregnancy were generally mild. Most pregnancies in women with SSc and MCTD in this cohort were uncomplicated. The high rates of prematurity and small for gestational age infants underscore the risk for growth restriction consistent with the vasculopathy associated with these diseases.

Adult↗

PubMed2005

Bleeding complications in patients on celecoxib and warfarin.

PURPOSE: Non-selective non-steroidal anti-inflammatory drugs (nNSAIDs) used in combination with warfarin are associated with an approximately 3-fold increased risk of upper gastrointestinal bleeding (UGIB) compared with warfarin alone. Celecoxib, a selective inhibitor of cyclo-oxygenase 2 (COX-2), is associated with less gastric mucosal injury and platelet dysregulation than nNSAIDs. We compared rates of bleeding complications in patients taking celecoxib and warfarin with those taking warfarin alone. SUBJECTS AND METHODS: We performed a retrospective analysis using data from our Protime Clinic and pharmacy databases from January 2001 to April 2004. We identified 123 patients who took celecoxib and warfarin concurrently (overlap group). We compared rates of bleeding complications in this group with 1022 control patients who were taking warfarin alone. Bleeding complications were defined as major if they resulted in hospitalization, blood transfusion or death. RESULTS: During approximately 1063 months of exposure to both celecoxib and warfarin, 10 bleeding complications were identified, only one of which was considered major. No patients had UGIB. In the control group, 116 bleeding complications were identified over approximately 16 520 months of exposure to warfarin alone, with 101 minor and 15 major events, including six episodes of UGIB. The relative risk of all bleeding complications was 1.34 (95% CI: 0.70-2.57) in the overlap vs. control groups, and for major bleeds was 1.04 (95% CI: 0.14-7.85). CONCLUSIONS: There is a mild but non-significant increase in bleeding complications in patients taking celecoxib and warfarin compared with those taking warfarin alone.

Aged↗

PubMed2005

Giant cell myocarditis: a rare cardiovascular manifestation in a patient with systemic lupus erythematosus.

Giant cell myocarditis (GCM) is a rare form of myocarditis with a median survival of less than one year. It has been reported to occur in patients with various underlying autoimmune diseases; however, no cases of GCM have been described in patients with clear evidence of underlying systemic lupus erythematosus (SLE). The presentation of GCM may mimic that of lupus myocarditis, including an initial response to immunosuppression. Despite initial clinical similarities, lupus myocarditis and GCM are histologically distinct entities with dramatic differences in prognosis. We report herein a patient with a longstanding history of SLE, who presented acutely with myocarditis, responded well to initial immunosuppression and then subsequently died of progressive heart failure that was found to be due to GCM. Endomyocardial biopsy can help define diagnosis and prognosis of lupus patients presenting with myocarditis, and early referral for cardiac transplantation should be considered in patients diagnosed with GCM.

Adult↗

PubMed2003

Efficacy of a specially designed hip protector for hip fracture prevention and compliance with use in elderly Hong Kong Chinese.

BACKGROUND: Hip protectors, while effective in prevention of hip fractures, have been designed for a Caucasian body build and may not be suitable for Asian subjects living in a subtropical climate. OBJECTIVE: Hip protectors and accompanying shorts were specially designed for use for the Chinese body build and subtropical climate, and tested for compliance and efficacy in fracture prevention. METHOD: A pragmatic study examining compliance with the wearing of hip protectors, and effectiveness in preventing hip fractures (using a case control design), in 302 subjects wearing hip protectors and 352 control subjects. RESULTS: Overall compliance varied from 55 to 70%. The relative risk for hip fracture was 0.18 (0.04-0.79), relative risk reduction 82%, and the number of subjects needing to wear a hip protector to prevent one fracture was 33 (19-117). CONCLUSION: Hip protectors adapted for use in Chinese people appear to reduce hip fractures in routine clinical practice.

Accidental Falls↗

PubMed2002

Genetically engineered analogs of ascomycin for nerve regeneration.

The polyketides FK506 (tacrolimus) and FK520 (ascomycin) are potent immunosuppressants that function by inhibiting calcineurin phosphatase through formation of an FKBP12-FK506/520-calcineurin ternary complex. They also have calcineurin-independent neuroregenerative properties in cell culture and animal models of nervous system disorders. Based on the crystal structure of the FKBP12-FK506-calcineurin complex, we deduced that the 13- and 15-methoxy groups of FK506 or FK520 are important for inhibition of calcineurin phosphatase but not for binding to FKBP12. By genetic modification of the FK520 gene cluster, we generated 13- and 15-desmethoxy analogs of FK520 that contain hydrogen, methyl, or ethyl instead of methoxy at one or both of these positions. These analogs bind FKBP12 tightly, have decreased calcineurin phosphatase inhibition and immunosuppressive properties, and enhance neurite outgrowth in cell cultures. A representative compound was also shown to accelerate nerve regeneration and functional recovery in the rat sciatic nerve crush model.

Acetyltransferases↗

PubMed2001

Structural analysis of the alpha(2) integrin I domain/procollagenase-1 (matrix metalloproteinase-1) interaction.

Previous studies have established that ligation of keratinocyte alpha(2)beta(1) integrin by type I collagen induces expression of matrix metalloproteinase-1 (MMP-1) and that MMP-1 activity is required for the alpha(2)beta(1) integrin-dependent migration of primary keratinocytes across collagenous matrices. We now present evidence that MMP-1 binds the alpha(2)beta(1) integrin via the I domain of the alpha(2) integrin subunit. Using an enzyme-linked immunosorbent assay with purified human MMP-1 and recombinant alpha(2) integrin I domain, we showed that the alpha(2) integrin I domain specifically bound in a divalent cation-dependent manner to both the pro and active forms of MMP-1, but not to MMP-3 or MMP-13. Although both the I domain and MMP-1 bind divalent cations, MMP-1 bound, in a divalent cation-dependent manner, to alpha(2) integrin I domains containing metal ion-dependent adhesion sites motif mutations that prevent divalent cation binding to the I domain, demonstrating that the metal ion dependence is a function of MMP-1. Using a series of MMP-1-MMP-3 and MMP-1-MMP-13 chimeras, we determined that both the linker domain and the hemopexin-like domain of MMP-1 were required for optimal binding to the I domain. The alpha(2) integrin/MMP-1 interaction described here extends an emerging paradigm in matrix biology involving anchoring of proteinases to the cell surface to regulate their biological activities.

Antigens, CD↗

PubMed2001

Kinetic analysis of matrix metalloproteinase activity using fluorogenic triple-helical substrates.

Matrix metalloproteinase (MMP) family members are involved in the physiological remodeling of tissues and embryonic development as well as pathological destruction of extracellular matrix components. To study the mechanisms of MMP action on collagenous substrates, we have constructed homotrimeric, fluorogenic triple-helical peptide (THP) models of the MMP-1 cleavage site in type II collagen. The substrates were designed to incorporate the fluorophore/quencher pair of (7-methoxycoumarin-4-yl)acetyl (Mca) and N-2,4-dinitrophenyl (Dnp) in the P(5) and P(5)' positions, respectively. In addition, Arg was incorporated in the P(2)' and P(8)' positions to enhance enzyme activity and improve substrate solubility. The desired sequences were Gly-Pro-Lys(Mca)-Gly-Pro-Gln-Gly approximately Leu-Arg-Gly-Gln-Lys(Dnp)-Gly-Ile/Val-Arg. Two fluorogenic substrates were prepared, one using a covalent branching protocol (fTHP-1) and one using a peptide self-assembly approach (fTHP-3). An analogous single-stranded substrate (fSSP-3) was also synthesized. Both THPs were hydrolyzed by MMP-1 at the Gly approximately Leu bond, analogous to the bond cleaved in the native collagen. The individual kinetic parameters for MMP-1 hydrolysis of fTHP-3 were k(cat) = 0.080 s(-1) and K(M) = 61.2 microM. Subsequent investigations showed fTHP-3 hydrolysis by MMP-2, MMP-3, MMP-13, a C-terminal domain-deleted MMP-1 [MMP-1(Delta(243-450))], and a C-terminal domain-deleted MMP-3 [MMP-3(Delta(248-460))]. The order of k(cat)/K(M) values was MMP-13 > MMP-1 approximately MMP-1(Delta(243-450)) approximately MMP-2 >> MMP-3 approximately MMP-3(Delta(248-460)). Studies on the effect of temperature on fTHP-3 and fSSP-3 hydrolysis by MMP-1 showed that the activation energies between these two substrates differed by 3.4-fold, similar to the difference in activation energies for MMP-1 hydrolysis of type I collagen and gelatin. This indicates that fluorogenic triple-helical substrates mimic the behavior of the native collagen substrate and may be useful for the investigation of collagenase triple-helical activity.

Amino Acid Sequence↗

PubMed2001

Deletion of rapQONML from the rapamycin gene cluster of Streptomyces hygroscopicus gives production of the 16-O-desmethyl-27-desmethoxy analog.

Five contiguous genes in the rapamycin gene cluster, rapQONML, of Streptomyces hygroscopicus ATCC29253 were replaced with a neomycin resistance marker by double homologous recombination. The resulting strain, if fed pipecolate, produced the analog 16-O-desmethyl-27-desmethoxyrapamycin instead of rapamycin. This indicates that the P450 hydroxylase encoded by rapN is specific for C-27, and that the O-methyltransferases encoded by rapQ and rapM methylate the hydroxyl groups on C-16 and C-27. By inference, the remaining P450 hydroxylase and methyltransferase genes (rapI and rapJ) are responsible for hydroxylation of C-9 and methylation of the C-39 hydroxyl, consistent with their homology to fkbD and fkbM, respectively, in the FK506 cluster. The relatively high level of 16-O-desmethyl-27-desmethoxyrapamycin produced indicates that the reactions at C-9 and C-39 do not require previous modification of the macrolactone precursor at either C-16 or C-27.

Anti-Bacterial Agents↗

PubMed2001

Tai Chi: towards an exercise program for the older person.

In the changing demographic and health care contexts of aged care, the creation of health promoting exercise programs for frail elderly people to improve wellbeing and quality of care is a common objective in community and residential aged care. This article describes the background to the development of a gentle exercise program that has therapeutic value and the potential to improve wellbeing and quality of care.

Activities of Daily Living↗

PubMed2000

Identification of the (183)RWTNNFREY(191) region as a critical segment of matrix metalloproteinase 1 for the expression of collagenolytic activity.

Matrix metalloproteinase 1 (MMP-1) cleaves types I, II, and III collagen triple helices into (3/4) and (1/4) fragments. To understand the structural elements responsible for this activity, various lengths of MMP-1 segments have been introduced into MMP-3 (stromelysin 1) starting from the C-terminal end. MMP-3/MMP-1 chimeras and variants were overexpressed in Escherichia coli, folded from inclusion bodies, and isolated as zymogens. After activation, recombinant chimeras were tested for their ability to digest triple helical type I collagen at 25 degrees C. The results indicate that the nine residues (183)RWTNNFREY(191) located between the fifth beta-strand and the second alpha-helix in the catalytic domain of MMP-1 are critical for the expression of collagenolytic activity. Mutation of Tyr(191) of MMP-1 to Thr, the corresponding residue in MMP-3, reduced collagenolytic activity about 5-fold. Replacement of the nine residues with those of the MMP-3 sequence further decreased the activity 2-fold. Those variants exhibited significant changes in substrate specificity and activity against gelatin and synthetic substrates, further supporting the notion that this region plays a critical role in the expression of collagenolytic activity. However, introduction of this sequence into MMP-3 or a chimera consisting of the catalytic domain of MMP-3 with the hinge region and the C-terminal hemopexin domain of MMP-1 did not express any collagenolytic activity. It is therefore concluded that RWTNNFREY, together with the C-terminal hemopexin domain, is essential for collagenolytic activity but that additional structural elements in the catalytic domain are also required. These elements probably act in a concerted manner to cleave the collagen triple helix.

Amino Acid Sequence↗

PubMed2000

The FK520 gene cluster of Streptomyces hygroscopicus var. ascomyceticus (ATCC 14891) contains genes for biosynthesis of unusual polyketide extender units.

FK520 (ascomycin) is a macrolide produced by Streptomyces hygroscopicus var. ascomyceticus (ATCC 14891) that has immunosuppressive, neurotrophic and antifungal activities. To further elucidate the biosynthesis of this and related macrolides, we cloned and sequenced an 80kb region encompassing the FK520 gene cluster. Genes encoding the three polyketide synthase (PKS) subunits (fkbB, fkbC and fkbA), the peptide synthetase (fkbP), the 31-O-methyltransferase (fkbM), the C-9 hydroxylase (fkbD) and the 9-hydroxyl oxidase (fkbO) had the same organization as the genes reported in the FK506 gene cluster of Streptomyces sp. MA6548 (Motamedi, H., Shafiee, A., 1998. The biosynthetic gene cluster for the macrolactone ring of the immunosuppressant FK506. Eur. J. Biochem. 256, 528-534). Disruption of a PKS gene in the cluster using the φC31 phage vector, KC515, led to antibiotic non-producing strains, proving the identity of the cluster. Previous labeling data have indicated that FK520 biosynthesis uses novel polyketide extender units (Byrne, K.M., Shafiee, A., Nielson, J., Arison, B., Monaghan, R.L., Kaplan, L., 1993. The biosynthesis and enzymology of an immunosuppressant, immunomycin, produced by Streptomyces hygroscopicus var, ascomyceticus. Dev. Ind. Microbiol. 32, 29-45). Genes in the flanking regions of the FK520 cluster were identified that appear to be involved in synthesis of these extender units. All but two of these genes were homologous to genes with known function. In addition to a crotonyl-CoA reductase gene (fkbS), at least two other genes are proposed to be involved in biosynthesis of the atypical PKS extender unit ethylmalonyl-CoA, which accounts for the ethyl side chain on C-21 of FK520. A set of five contiguous genes (fkbGHIJK) is proposed to be involved in biosynthesis of an unusual PKS extender unit bearing an oxygen on the alpha-carbon, and leading to the 13- and 15-methoxy side chains. These putative precursor synthesis genes in the flanking regions of the FK520 cluster are not found in the flanking regions of the rapamycin cluster (Molnár, I., Aparicio, J.F., Haydock, S.F., Khaw, L.E., Schwecke, T., König, A., Staunton, J., Leadlay, P.F., 1996. Organisation of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of genes flanking the polyketide synthase. Gene 169, 1-7), consistent with labeling data showing that rapamycin biosynthesis uses only malonyl and methylmalonyl extender units.

Acyl Coenzyme A↗

PubMed2000

Cloning and heterologous expression of the epothilone gene cluster.

The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol. The gene cluster responsible for epothilone biosynthesis in the myxobacterium Sorangium cellulosum was cloned and completely sequenced. It encodes six multifunctional proteins composed of a loading module, one nonribosomal peptide synthetase module, eight polyketide synthase modules, and a P450 epoxidase that converts desoxyepothilone into epothilone. Concomitant expression of these genes in the actinomycete Streptomyces coelicolor produced epothilones A and B. Streptomyces coelicolor is more amenable to strain improvement and grows about 10-fold as rapidly as the natural producer, so this heterologous expression system portends a plentiful supply of this important agent.

Bacterial Proteins↗

PubMed2000

[The "quality of life" concept in medical students and postgraduate residents in a university hospital].

We investigated the quality of life's concept and its uses by both residents and interns as well as last year medical students in the University Hospital in Caracas (HUC). A random sample by strata, without replacement of 123 persons, completed a self administered questionnaire which included a set of closed questions and one of open questions related to the quality of life's concept. The mean age was 29 years for both sexes (3.55 standard deviation or SD). There was not a statistically significant difference between males and females. More than 50% read about quality of life in either newspapers, journals and fiction literature. There was no difference among the groups (p = 0.25). Only 68% had heard in a different sort of academical institution the term "quality of life" such as in the school of medicine, highschool or in some discussion groups with no differences among the groups (p = 0.15). However, there was no agreement as from whom and where they learned about quality of life (p < 0.001). Although everybody considered that the quality of life was an important element in medical actions such as diagnostic or therapeutics, its importance was reduced for diagnosis compared to treatment (p < 0.0001). All the elements that were considered as part of the concept were also considered as important, regardless of the group and was statistically significant (p < 0.05). The open question analysis showed that the non-medical definitions represent 85.15% of the group, 50% out of them included terms of potentiality or condition. Among the elements included in the definition was the social in 27.65%, psychological in 23.53% and, the economical in 12.35% of the questionnaires. The great majority of the "quality of life" definitions did not include a clearly defined subject and in many cases it was exclusively related to ill persons. Finally, there is an informal and not well oriented form of learning about "quality of life" in residents, interns and last year medical students with a lack of a good applicability in the medical practice. Therefore, there is a need for a formal training on quality of life along the medical studies and its uses in the medical practice in general and with special emphasis on diagnosis and therapeutics.

Adult↗

PubMed1999

Engineering of selective TIMPs.

Differences in proteinase susceptibility between free TIMP-1 and the TIMP-1-MMP-3 complex and mutagenesis studies suggested that the residues around the disulfide bond between Cys1 and Cys70 in TIMP-1 may interact with MMPs. The crystal structure of the complex between TIMP-1 and the catalytic domain of MMP-3 has revealed that the alpha-amino group of Cys1 bidentately chelates the catalytic zinc of MMP-3 and the Thr2 side chain occupies the S1' pocket. Generation of the N-terminal domain of TIMP-1 (N-TIMP-1) variants with 15 different amino acid substitutions for Thr2 has indicated that the nature of the side chain of residue 2 has a major effect on the affinity of N-TIMP-1 for three different MMPs (MMPs-1, -2 and -3). The results also demonstrate that the mode of binding of N-TIMP-1 residue 2 differs from the binding of the P1' residue of a peptide substrate.

Amino Acid Sequence↗

PubMed1999

Residue 2 of TIMP-1 is a major determinant of affinity and specificity for matrix metalloproteinases but effects of substitutions do not correlate with those of the corresponding P1' residue of substrate.

The unregulated activities of matrix metalloproteinases (MMPs) are implicated in disease processes including arthritis and tumor cell invasion and metastasis. MMP activities are controlled by four homologous endogenous protein inhibitors, tissue inhibitors of metalloproteinases (TIMPs), yet different TIMPs show little specificity for individual MMPs. The large interaction interface in the TIMP-1.MMP-3 complex includes a contiguous region of TIMP-1 around the disulfide bond between Cys1 and Cys70 that inserts into the active site of MMP-3. The effects of fifteen different substitutions for threonine 2 of this region reveal that this residue makes a large contribution to the stability of complexes with MMPs and has a dominant influence on the specificity for different MMPs. The size, charge, and hydrophobicity of residue 2 are key factors in the specificity of TIMP. Threonine 2 of TIMP-1 interacts with the S1' specificity pocket of MMP-3, which is a key to substrate specificity, but the structural requirements in TIMP-1 residue 2 for MMP binding differ greatly from those for the corresponding residue of a peptide substrate. These results demonstrate that TIMP variants with substitutions for Thr2 represent suitable starting points for generating more targeted TIMPs for investigation and for intervention in MMP-related diseases.

Cell Line↗

PubMed1999

Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome. Genes Chromosomes Cancer 25:75-81, 1999.

Chan TL, Yuen ST, Chung LP, Ho JWC, Kwan K, Fan YW, Chan ASY, Leung SY. 1999. Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome. Genes Chromosomes Cancer 25:75-81, 1999. It has come to our attention that the three patients described in the article above, were also included in a report by Leung et al., American Journal of Pathology, 153:1181-1189, 1998. Reference to the American Journal of Pathology article was inadvertently omitted

Journal Article↗

PubMed1999

Synthesis of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene and its reaction with DNA.

Substitution of a methyl group in the bay region can enhance the tumorigenicity of polycyclic aromatic hydrocarbons such as chrysene, benz[a]anthracene, and others. This phenomenon has been related to facile DNA adduct formation of bay region diol epoxides with a methyl group and epoxide ring in the same bay. While anti-7, 8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and its DNA adduct formation have been studied extensively, it is not known whether a methyl substituent in the bay region alters the reactivity of DNA in this system. This is of interest because 11-methylbenzo[a]pyrene, which has a bay region methyl group, is more tumorigenic than benzo[a]pyrene. To examine the question, we have devised and employed an efficient synthesis based on photochemical cyclization, and prepared anti-7,8-dihydroxy-9, 10-epoxy-7,8,9,10-tetrahydro-11-methylbenzo[a]pyrene, the likely ultimate carcinogen of 11-methylbenzo[a]pyrene. We have then reacted anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene with calf thymus DNA and found that it gives three major adducts. These were identified as having resulted from cis- and trans-ring opening of the (S,R,R, S)-enantiomer and from trans-ring opening of the (R,S,S, R)-enantiomer. The standard deoxyguanosine adduct markers were prepared, and their structures were tentatively assigned on the basis of their CD and 1H NMR spectra. The adduct distribution of anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene is quite different from that observed in the reaction of DNA with the corresponding diol epoxides of benzo[a]pyrene or with 5-methylchrysene. The heterogeneity of adducts obtained with anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydro-11-methylbenzo[a]pyrene thus may be related to the enhanced tumorigenicity of 11-methylbenzo[a]pyrene.

Benzopyrans↗