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Biomedical subjects

A Lau

Publications and source records attributed to A Lau.

At least 19 recordsLinked to original sources
PubMed1999

Frequency of meiotic trisomy depends on involved chromosome and mode of ascertainment.

Although maternal meiotic errors predominate in most studies of nonmosaic trisomy, studies of trisomy ascertained through confined placental mosaicism (CPM) have shown a high rate of somatic errors. However, origin of trisomy of many of the chromosomes involved in CPM has not been evaluated previously in cases ascertained through spontaneous abortions (SAs). Therefore, it was impossible to determine if the relative lack of meiotic errors in trisomy-CPM cases was a characteristic of the specific chromosome involved or due simply to ascertainment through a mosaic state. In the present study, parental and meiotic/somatic stages of origin of trisomy were determined in 89 SAs involving trisomy of chromosomes 2, 4 to 10, 12, 15, 17, and 20. Comparisons were then made to origin of trisomy in cases of confined and generalized trisomy mosaicism. Although somatic errors are generally more common in mosaic cases, this depends on the specific chromosome involved. The results suggest that there are chromosome-specific differences in the relative frequency of somatic chromosome gain or loss and/or the ability of an early somatic loss of one chromosome from a trisomic conceptus to "rescue" the pregnancy. As mean maternal age was less in the somatic than meiotic origin cases (P < 0.01), the age distribution of the study population should also influence the probability of detecting a somatic error. No phenotypic differences were apparent when cases were subdivided based on either parent or stage of origin of the trisomy.

Abortion, Spontaneous↗
PubMed1999

Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls.

OBJECTIVE: To determine whether the risk of falling (with a possible increased chance of subdural hematoma) should influence the choice of antithrombotic therapy in elderly patients with atrial fibrillation. DESIGN: A Markov decision analytic model was used to determine the preferred treatment strategy (no antithrombotic therapy, long-term aspirin use, or long-term warfarin use) for patients with atrial fibrillation who are 65 years of age and older, are at risk for falling, and have no other contraindications to antithrombotic therapy. Input data were obtained by systematic review of MEDLINE. Outcomes were expressed as quality-adjusted life-years. RESULTS: For patients with average risks of stroke and falling, warfarin therapy was associated with 12.90 quality-adjusted life-years per patient; aspirin therapy, 11.17 quality-adjusted life-years; and no antithrombotic therapy, 10.15 quality-adjusted life-years. Sensitivity analysis demonstrated that, regardless of the patients' age or baseline risk of stroke, the risk of falling was not an important factor in determining their optimal antithrombotic therapy. CONCLUSIONS: For elderly patients with atrial fibrillation, the choice of optimal therapy to prevent stroke depends on many clinical factors, especially their baseline risk of stroke. However, patients' propensity to fall is not an important factor in this decision.

Accidental Falls↗
PubMed1999

Differential regulation of human T-plastin gene in leukocytes and non-leukocytes: identification of the promoter, enhancer, and CpG island.

Plastins (fimbrins) are a family of actin-bundling proteins conserved from yeast to humans. In humans, three tissue-specific plastin isoforms have been identified. The T isoform (T-plastin) is unique in that it is expressed in all tissues except leukocytes. To investigate how the T-plastin gene is differentially regulated in leukocytes and non-leukocytes, we isolated a genomic clone that included 9 kb of the upstream flanking region, 0.1 kb of the first exon, and 5.9 kb of the first intron. From this clone, we obtained a continuous sequence of 5535 bp, including 3138 bp of the upstream flanking region, the first exon, and 2286 bp of the first intron. A cluster of four transcription initiation sites was located by S1 mapping. A region spanning these sites and extending 1.4 kb into the first intron had the characteristics of a CpG island. Three CG-containing restriction sites within this island were analyzed and found all or variably methylated in four T-plastin-negative leukemia cell lines. In contrast, the same sites were not methylated in three T-plastin-expressing cell lines or in a sample of normal blood lymphocytes. A basal promoter was located 250 bp upstream from the transciption initiation sites. It comprised a CCAAT box, an Sp1 motif, and four AP2 motifs. No TATA or Inr sequence was found. The basal promoter exhibited weak activity when assayed in fibrosarcoma cells. Stronger promoter activities were found in the presence of the SV40 enhancer or a T-plastin enhancer located some 500 bp from the basal promoter. In T-plastin-negative leukemia cells, the T-plastin basal promoter could be activated by the SV40 enhancer but not by the T-plastin enhancer. DNA footprinting identified the T-plastin enhancer as two inverted symmetric octamers (AGATAACCTC and GAGGTCAGCT) separated by 17 nucleotides.

Base Sequence↗
PubMed1998

Analysis of neuronal nitric oxide synthase isoform expression and identification of human nNOS-mu.

The neuronal form of nitric oxide synthase (nNOS) is responsible for the production of NO, which acts as a neurotransmitter for penile erection and urethra relaxation. An nNOS splice variant form, nNOS-mu, was first reported to be specifically expressed in skeletal muscle and heart in the rat, but later also identified in rat penile cavernosum. We report here an apparently universal expression of nNOS-mu mRNA in rat tissues, including brain, which was previously reported to be lacking nNOS-mu. Immunoblot analysis revealed that some commercially available nNOS antibodies had high levels of nonspecific activities, which could lead to the appearance of seemingly multiple forms of nNOS. Immunohistochemical analysis with these antibodies also produced nonspecific stainings. In humans, nNOS-mu; expression appeared to be confined to skeletal muscle and heart. Human penile tissues obtained from patients with erectile dysfunction did not express nNOS-mu. The human nNOS-mu-specific cDNA sequence was 89% homologous to its rat counterpart.

Alternative Splicing↗
PubMed1998

The mechanism of trans-activation of the MDR1 gene by human T-cell leukemia virus.

Overexpression of P-glycoprotein (P-gp), the protein product of the multidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. We have recently demonstrated that the MDR1 promoter is transcriptionally activated by the HTLV-I tax protein, providing an explanation for the development of drug resistance in HTLV-I infections. Here we report that HTLV-I mediated MDR1 activation is dependent on the presence of an NF-IL6-binding site located between base pairs -148 and -141 relative to the transcription start site. This finding opens up the possibility of moderating P-gp expression through interference with NF-IL6 binding to its trans recognition element and subsequent repression of MDR1 transcription.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Enhanced MDR1 gene expression in human T-cell leukemia virus-I-infected patients offers new prospects for therapy.

Overexpression of P-glycoprotein (P-gp), the protein product of the multidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. This phenotype is reminiscent of human T-cell leukemia virus (HTLV)-transformed leukemic cells, for which no consistently effective chemotherapeutic regime has been found. The presence of an active multiple drug resistance (MDR) phenotype in freshly isolated peripheral blood mononuclear cells (PBMC) from HTLV-I-infected subjects was investigated. Significant P-gp-mediated efflux activity and enhanced MDR1 mRNA expression was observed in nine of 10 HTLV-infected subjects. The development of MDR phenotypes was found to be independent of disease type or status with significant MDR activities being observed in adult T-cell leukemia (ATL), HTLV-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), and asymptomatic HTLV-infected individuals. P-gp-mediated drug efflux was also found to be restricted to CD3+ T-cell populations. Furthermore, we show the novel finding that the MDR1 gene promoter is transcriptionally activated by the HTLV-I tax protein, suggesting a molecular basis for the development of drug resistance in HTLV-I infections. These observations open up the possibility of new chemotherapeutic approaches to HTLV-associated diseases through the use of P-gp inhibitors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Nizatidine in combination with amoxycillin and clarithromycin in the treatment of Helicobacter pylori infection.

BACKGROUND: The efficacy of H2-antagonists in combination with antibiotics in curing Helicobacter pylori infection remains controversial, and it is uncertain whether double dose H2-antagonist therapy is superior to standard dose. AIM: To determine the efficacy of two doses of nizatidine in combination with two antibiotics in the treatment of H. pylori. METHODS: A randomized controlled trial was conducted in 160 patients comparing nizatidine 150 mg with 300 mg b.d. (standard vs. double dose), in combination with clarithromycin (500 mg) and amoxycillin (1000 mg) b.d. for 14 days, in Australia and Taiwan. Compliance was based on a clinical assessment and pill count. H. pylori status was determined by histology (antrum and corpus) and CLO-test. RESULTS: Baseline clinical and endoscopic findings were similar in both arms of the study. Based on an intention-to-treat analysis, cure of H. pylori was achieved in 78% (95% CI: 70.4-85.4%) in the standard nizatidine dose arm and 70% (95% CI: 61.6-78.2%) in the double dose arm (P=0.2). Similar cure rates were observed in ulcer and non-ulcer patient groups. Compliance was excellent in the single and double dose arms (85 and 91%, respectively). CONCLUSIONS: The combination of nizatidine in standard or double dose with clarithromycin and amoxycillin is similarly efficacious in curing H. pylori infection.

Adult↗
PubMed1998

Quinine for nocturnal leg cramps: a meta-analysis including unpublished data.

OBJECTIVE: With respect to the use of quinine for the treatment of nocturnal leg cramps, to determine whether the findings of a previously performed meta-analysis of published data are altered with the addition of unpublished data, and whether publication bias is present in this area. DESIGN: A meta-analysis of eight (four published and four unpublished) randomized, double-blind, placebo-controlled trials, seven of which had a crossover design. SETTING: Randomized trials that were available as of July 1997. SUBJECTS: Ambulatory patients (659) who suffered from regular nocturnal leg cramps. MAIN RESULTS: When individual patient data from all crossover studies were pooled, persons had 3.60 (95% confidence interval [CI] 2.15, 5.05) fewer cramps in a 4-week period when taking quinine compared with placebo. This compared with an estimate of 8.83 fewer cramps (95% CI 4.16, 13.49) from pooling published studies alone. The corresponding relative risk reductions were 21% (95% CI 12%, 30%) and 43% (95% CI 21%, 65%), respectively. Compared with placebo, the use of quinine was associated with an increased incidence of side effects, particularly tinnitus. Publication bias is present in the reporting of the efficacy of quinine for this indication, as almost all published studies reported larger estimates of its efficacy than did unpublished studies. CONCLUSIONS: This study confirms that quinine is efficacious in the prevention of nocturnal leg cramps. However, its benefit may not be as large as reported from the pooling of published studies alone. Given the side effect profile of quinine, nonpharmacologic therapy (e.g., regular passive stretching of the affected muscle) is the best first-line treatment. For persons who find this ineffective and whose quality of life is significantly affected, a trial of quinine is warranted. Prescribing physicians must closely monitor the risks and benefits in individual patients. Publication bias is present in this area even though there is controversy about the role of quinine in the treatment of leg cramps. To minimize the possibility of this bias, persons performing medication-related meta-analyses should seek high-quality unpublished data from drug regulatory agencies and pharmaceutical companies.

Humans↗
PubMed1998

Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2.

In this double-blind, placebo-controlled, randomized, multicenter study, 35 patients with end-stage renal disease undergoing maintenance hemodialysis were treated three times weekly for 4 weeks with either 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) intravenously at doses ranging from 0.04 to 0.24 microg/kg or placebo. Eligible patients with secondary hyperparathyroidism (HPT; intact parathyroid hormone [iPTH] level > 300 pg/mL) were initially withdrawn from any existing vitamin D therapy over a 4-week washout period and then randomized to treatment for 4 weeks with either paricalcitol or placebo. Overall, there was a clinically and statistically significant reduction in iPTH level for patients receiving paricalcitol compared with placebo (P = 0.006). The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH level for 75% of the patients receiving paricalcitol per dosing group. The study end point for efficacy was at least a 30% reduction from maximum baseline in iPTH for 75% of patients receiving paricalcitol per dosing group. Sixty-eight percent (15 of 22) of patients receiving paricalcitol attained this efficacy end point regardless of dosage received (0.04, 0.08, 0.16, and 0.24 microg/kg). Eighty-three percent (5 of 6) of the patients in each of the paricalcitol groups receiving 0.16- and 0.24-microg/kg dosages attained the efficacy end point. Only two patients receiving placebo attained the iPTH end point. There were no clinically relevant differences in serum calcium (Ca) or phosphorus (P) levels between the group treated with paricalcitol and that treated with placebo. Although there was a statistically significant difference between the change from baseline to final-visit Ca levels in the paricalcitol group and the placebo group (P < 0.001), the final-visit mean Ca level in the paricalcitol group was within the normal range (9.44 mg/dL). There was no statistically significant difference between groups for the change from baseline in P level (P = 0.625). Only one patient treated with paricalcitol developed hypercalcemia before or coincident with the iPTH end point. Three other patients receiving paricalcitol experienced elevated serum Ca levels subsequent to reaching the iPTH end point, with iPTH reductions of 83% to 98%. There were no significant differences between patients treated with paricalcitol and patients treated with placebo in adverse reactions. These results show that paricalcitol safely and effectively reduces iPTH levels in hemodialysis patients with secondary HPT.

Adolescent↗
PubMed1998

Analysis and mapping of plastin phosphorylation.

Plastins (fimbrins) are a family of three tissue-specific actin-binding proteins. Both L- and T-plastin have been shown to be involved in cytoskeletal reorganization in signal-transduction pathways. Phosphorylation of the leukocyte-specific L-plastin plays important roles in regulating L-plastin function and leukocyte activation. We created L-plastin mutants, changing each of the Ser-5 and Ser-7 residues to alanine. Expression of either mutant in WI38VA13 fibroblasts did not result in phosphorylation. The transfected wildtype L-plastin was phosphorylated in WI38VA13, but its two-dimensional gel pattern suggested that it was phosphorylated on one residue, whereas the endogenous L-plastin in leukocytes was likely phosphorylated on two residues. The nonleukocyte-specific T-plastin, which has an equivalent Ser-7 residue, was not phosphorylated in T-plastin-expressing fibroblasts or in transfected leukocytes. Expression of CK-IIalpha, the catalytic subunit of casein kinase II, resulted in changes of the protein expression profile in leukocytes but not the phosphorylation status of L- or T-plastin. Phorbol myristate acetate induced L-plastin phosphorylation in both leukocytes and fibroblasts, lending support to the view that protein kinase C is the likely candidate kinase for L-plastin phosphorylation.

Amino Acid Sequence↗
PubMed1998

Excessive production of nitric oxide by macrophages from DP-BB rats is secondary to the T-lymphopenic state of these animals.

Activated macrophages are the first mononuclear cells to migrate to the pancreas of DP-BB rats at the initiation of insulitis. These cells produce an excess of NO, which has been implicated as a mediator of both beta-cell damage and inhibition of T-cell proliferation in this rat strain. Genetic studies have shown that the impaired proliferative response of T-cells segregates with one of the diabetes-susceptibility genes of the DP-BB rat, lyp, which is responsible for a peripheral T-lymphopenia. This observation suggests that the dysregulated expression of inducible NO synthase (iNOS) is under the control of lyp itself or a gene in linkage disequilibrium with lyp. Using two models of hemopoietic chimeras--DP-BB rats reconstituted with isocongenic T-cells and irradiated (WF x DP-BB)F1 animals reconstituted with bone marrow of both parental strains--we demonstrated that the production of NO by DP-BB macrophages is normal when these cells originate from a non-T-lymphopenic environment. Consequently, these macrophages no longer inhibit the stimulation of DNA synthesis in activated T-cells. Macrophages of young WF rats were found to produce high levels of NO, which inhibited T-cell proliferation in vitro. This observation strongly suggests that upregulation of NO synthesis in DP-BB macrophages represents the abnormal persistence of a phenomenon restricted to the first few weeks of life in non-diabetes-prone rats. Taken together, these results demonstrate that the elevated production of NO by DP-BB macrophages results from the lyp mutation and represents a crucial mechanism through which T-lymphopenia contributes to the development of diabetes.

Animals↗
PubMed1997

Thrombin causes a marked delay in skeletal myogenesis that correlates with the delayed expression of myogenin and p21CIP1/WAF1.

Thrombin is a multifunctional serine protease whose activity is regulated in the extravasculature by an extracellular inhibitor, protease nexin-1. Because protease nexin-1 expression has been shown to be regulated during skeletal muscle cell differentiation, we reasoned that thrombin inactivation may be an important requirement for this developmental process. To test this hypothesis, we examined the effects of thrombin on differentiating C2C12 myoblasts. We report here that myogenesis, as scored by myotube formation, is considerably delayed by thrombin. This regulation correlated with delayed expression of myogenin and p21(CIP1/WAF1), both considered critical components of the skeletal muscle cell differentiation program. Regulation occurred at the RNA level, indicating that the effect of thrombin is either transcriptional or post-transcriptional. Furthermore, we present evidence suggesting that this regulation is mediated by the thrombin receptor. Although thrombin is mitogenic for certain cell types, we found that delay of myogenesis in C2C12 cells did not involve a mitogenic signal. Taken together, these results imply that inhibition of the serine protease thrombin may be required for proper progression through the myogenic differentiation program. The data point to potentially important roles that thrombin and protease nexin-1 may play during skeletal muscle development.

Animals↗
PubMed1997

Analytical performance and clinical utility of a sensitive immunoassay for determination of human cardiac troponin I.

OBJECTIVES: To determine the serum and plasma level of human cardiac troponin I (cTnI) resulting from myocardial damage, we have developed a sensitive and specific one-step enzyme immunoassay to measure cardiac troponin I. DESIGN AND METHODS: The COBAS cTnI assay is a semi-automated one-step solid phase immunoassay compatible with the COBAS Core. The assay is performed in a sandwich type format using a polyclonal goat antibody capture and two highly specific horseradish peroxidase conjugated monoclonal antibody detectors directed against different epitopes of the cTnI molecule. Calibrators were made with purified recombinant cTnI. RESULTS: The level of cTnI was determined in 84 healthy donors with no evidence of myocardial injury, resulting in a lower limit of detection (LLD) of 0.09 microgram/L. The upper reference limit (URL) of the normal reference range was calculated as 0.20 microgram/L. The dynamic range of the consequent EIA was between 0.09 and 6.0 micrograms/L with a total assay time of 45 min. Intra-assay and inter-assay variances (CVs) were < or = 4%. Cross-reactivity with fast and slow skeletal troponin I was absent in concentrations up to 2.0 mg/L. Common interferents yielded negative results in the cTnI assay. Clinical utility was confirmed by measuring the circulating serum or plasma levels of cardiac troponin I in serial samples from marathon runners, clinical samples from trauma patients, and patients presenting to the Emergency Department with complaints of chest pain. Results were further evaluated using clinical diagnosis at discharge and quantified concentrations of other cardiac markers by a Stratus analyzer and ELISA procedures. CONCLUSIONS: Results from normal and clinical samples assayed in house for cTnI concentrations indicate that the Spectral EIA is a highly sensitive means of quantifying cTnI levels in serum and plasma for acute cardiac syndrome. The cardiac specificity of cTnI over other well-known cardiac markers is reflected in experimental results and parallel clinical diagnosis.

Animals↗
PubMed1996

Production of non-infectious human immunodeficiency virus-like particles which package specifically viral RNA.

A recombinant vector that rapidly produces large amounts of human immunodeficiency virus (HIV) virus-like particles (VLPs) was constructed. This vector lacks LTR sequences and a functional nef gene. The VLPs produced are non-infectious but similar in structure to mature, infectious HIV virions. They package specifically HIV RNAs containing appropriate signals and do not package abundant cellular mRNAs (e.g. actin). In the system described here, efficient particle production and release is decoupled from infection. Use of this VLP system offers many advantages over the study of infectious virions, permitting the expression of mutant phenotypes which interfere with virus infectivity.

Animals↗
PubMed1995

Conjugation of doxorubicin to monoclonal anti-carcinoembryonic antigen antibody via novel thiol-directed cross-linking reagents.

In order to improve the available methods to produce an immunoconjugate the use of longer heterobifunctional cross-linking reagents were investigated. Two new maleimidobenzoyl spacers have been synthesized in a one step process from 4-maleimidobenzoic acid. The new heterobifunctional cross-linking reagents were fully characterized by their IR, 1H NMR, 13C NMR and mass spectra. These spacers are selectively attached to NH2-3' of the daunosamine moiety of doxorubicin. The spacer-doxorubicin derivatives were also characterized by 1H NMR spectrometry before coupling to thiol groups of thiolated anti-carcinoembryonic antigen (CEA) monoclonal antibody (11-285-14). These conjugates contain 1.51-3.44 molecules of drug for each molecule of monoclonal antibody (MAb).

Antibodies, Monoclonal↗
PubMed1995

Novel doxorubicin-monoclonal anti-carcinoembryonic antigen antibody immunoconjugate activity in vitro.

Doxorubicin was modified with five different heterobifunctional reagents to produce drug analogs containing 3'-N-amide or C-13 hydrazone linkage with maleimide. Synthesis and characterization of two new reagents, 4-maleimidobenzohydrazide trifluoroacetate salt (13) and N-(4-maleimidobenzoyl)-6-aminocaprohydrazide trifluoroacetate salt (14) are described here. All Dox maleimido derivatives were conjugated to thiolated anti-carcinoembryonic antigen monoclonal antibody, 11-285-14, via a Michael addition reaction. Antibody-directed cytotoxicity was demonstrated with the MTT assay using combinations of antigen-positive and antigen-negative cell lines. The immunoconjugates prepared from Dox 3'-N-amide analogs are not active in vitro, however, Dox(hydrazone-linked) immunoconjugates are selectively toxic to the CEA positive cell line.

Adenocarcinoma↗