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Biomedical subjects

A Lau

Publications and source records attributed to A Lau.

At least 19 recordsLinked to original sources
PubMed2006

Effect of substrate and fibrin polymerization inhibitor on determination of plasma thrombin generation in vitro.

BACKGROUND: Thrombin generation potential, a critical haemostatic measure, can be determined by continuous detection of total thrombin or direct subsampling. However, differences between methods exist in area under the curve or peak thrombin calculated. Also, impact of anticoagulants on thrombin generation may vary depending on mode of analysis. OBJECTIVE: We studied the effect of components on thrombin generation in the presence or absence of anticoagulants. METHODS: The continuous method was conducted with plasma +/- fibrin(ogen) +/- fibrin polymerization inhibitor. Plasma contained slow-reacting TG5134 substrate at 37 degrees C and reaction was started with dilute thromboplastin in CaCl(2)/Tris buffer. Absorbance (405 nm) was recorded over time and free thrombin calculated from total thrombin activity. For the subsampling method, similar plasma mixtures +/- TG5134 were reacted and free thrombin measured directly as the difference in activity against S2238 substrate of timed subsamples taken into EDTA or EDTA + antithrombin + heparin. RESULTS: Slow-reacting substrate in the continuous method acted as a competitor for thrombin, giving delayed but greater free thrombin than direct subsampling. These differences persisted to varying extents with all anticoagulants tested. In either method, presence of polymerization inhibitor increased the amount of free thrombin. Continuous method detection of alpha(2)macroglobulin complexes was hampered by sensitivity limits leading to inordinate free thrombin calculations. Especially with hirudin, although free thrombin remained at the end of the subsampling method, continuous method calculations assumed no residual free thrombin. CONCLUSION: In vitro plasma thrombin generation is delayed and increased by slow-acting substrate and fibrin polymerization inhibitor.

Adult↗
PubMed2006

[Alcohol use disorder: risks in anesthesia and intensive care medicine].

Approximately 20% of medical and surgical patients in hospital have an alcohol use disorder (AUD). Diagnosis of chronic alcohol abuse is performed by specific medical history, examination and validated tests. Biomarkers are a means of diagnosing chronic alcoholism in sedated, intubated and emergency patients. Chronic alcohol consumption damages the central nervous and cardiovascular system, the liver and the immune system. In medical ICUs more than 50% of liver injuries and chronic pancreatitis are due to chronic alcohol abuse. The alcohol withdrawal syndrome is emerging in 25% of AUD patients in intensive care after reduction of sedative drugs. Long term alcohol abuse also leads to cardiac arrhythmias, dilatative cardiomyopathy and hypotonic circulatory dysregulation. Bleeding complications are two-fold increased during and after surgery. Immune suppression results in an increased incidence of infectious complications like pneumonia, wound infection and urinary tract infection. In particular, septic encephalopathy is often misinterpreted as alcohol withdrawal syndrome. Due to the fact that AUD patients show a two to five-fold higher rate of postoperative complications they require increased attention to avoid latency of treatment and the development of multiple organ failure. Prophylaxis in terms of drug therapy or abstinence intervals and brief intervention strategies can help to prevent or ease some of these complications and can decrease the rate of long-term injuries.

Alcohol-Induced Disorders↗
PubMed2005

Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients.

BACKGROUND: Chronic hepatitis B infection (CHB) is a major health problem in Australia and worldwide. CHB is associated with significant long-term morbidity and mortality. Well tolerated treatment is now available, however the development of resistance is common and the optimal timing of treatment is yet to be determined. Identifying the factors that influence the natural history of CHB may help determine which patients need treatment and when to start it. OBJECTIVE: To determine the demographics, clinical features and virological profile of Australian patients infected with CHB and the influence of these factors on disease activity and severity. STUDY DESIGN: Review of prospectively collected demographic, clinical and virological features of all patients positive for hepatitis B surface antigen (HBsAg) for more than 6 months who were referred to St. Vincent's Hospital liver clinics. Age, sex and ethnicity were correlated with hepatitis B e antigen status (HBeAg), HBV replication status (ALT and HBV DNA), genotype and liver histology. RESULTS: 703 chronic hepatitis B surface antigen positive patients were identified. The patients were predominantly male with an average age of 44. Eighty two percent of patients were born overseas, primarily from Asian (65%) and Mediterranean countries (14%). Two thirds (426) had an elevated ALT (median 79) at presentation. HBeAg was positive in 37%. Active viral replication, defined as abnormal ALT or positive HBVDNA, was present in 74%, 48% of whom were HBeAg negative. In a subset of 103 patients genotyped, 8% had genotype A, 29% B, 41% C and 22% D. Genotype correlated with ethnicity; patients infected with genotypes A were predominantly Caucasian, B and C were Asian, and D were Mediterranean. Of 296 (42%) patients who underwent liver biopsy, 76 (27%) had advanced fibrosis. Advanced fibrosis was associated with increasing age and Mediterranean ethnicity. CONCLUSION AND RECOMMENDATIONS: Perinatal or early childhood transmission is predominant mode of infection in Australia. Two thirds of this cohort had active replication and were at increased risk of developing cirrhosis and/or hepatoma. Advanced disease was associated with age and ethnicity. HBeAg negative CHB accounts for almost half of all those with active viral replication. This parallels the rise in this form of CHB in Asia and the Mediterranean basin. Screening should be offered to people born in, or with parents born in areas of high endemnicity. To detect the development of active disease, patients with positive HBsAg but normal ALT should have liver function tests done 6 monthly and those with elevated ALT should be referred for consideration of therapy, irrespective of HBeAg status.

Antiviral Agents↗
PubMed2005

Long-term follow-up of secondary malignancies in adults after allogeneic bone marrow transplantation.

The purpose of this study was to evaluate the estimated incidence of secondary malignancies post-allogeneic bone marrow transplantation (BMT) in a cohort of adult patients previously reported now with an additional 8.5 years of follow-up. A cohort of 557 patients older than age 16 years underwent allogeneic BMT between June 1970 and November 1993. Histologic reports confirmed the diagnosis of a secondary malignancy. Multivariate Cox proportional hazards method was utilized to investigate predictors for the development of secondary malignancies. In all, 31 patients in this cohort developed a secondary malignancy a median of 6.79 years after their transplant. The estimated cumulative incidence rate of secondary malignancy was 4.2% at 10 years post transplant. When compared to the general population, the estimated observed/expected ratio of new cancer diagnoses was 5.13. On multivariate analysis, older age at the time of transplant was the only significant predictor for development of secondary cancer (P=0.01). The most common malignancies observed were nonmelanomatous skin cancers and squamous cell cancers of the buccal cavity. The risk of developing a secondary malignancy after allogeneic BMT is significant, particularly in older patients. Long-term survivors of transplant require regular monitoring for early signs of cancer, particularly of the skin and oral cavity.

Adult↗
PubMed2003

Investigation of the affinities of two new beta-carbolines for rat brain imidazoline(2) receptors.

The beta-carbolines are possible endogenous ligands and modulators of the imidazoline binding sites (I-BSs). Relatively little is known about this class of compound and its interaction with the I-BS. Presented here are the binding data for two aryl ring substituted dihydro-beta-carbolines at the imidazoline(2) binding site (I(2)-BS) and alpha(2)-adrenoceptor: BG-326 (5-bromo-4,9-dihydro-3H-b-carboline) and BG-350 (5-methoxy-4,9-dihydro-3H-b-carboline). Both compounds show good affinity and selectivity for the I(2)-BS.

Animals↗
PubMed2002

Human PDE5A gene encodes three PDE5 isoforms from two alternate promoters.

Sildenafil improves erectile function by inhibiting the cGMP-catalytic activity of phosphodiesterase type V (PDE5). We used rapid amplification of cDNA Ends-polymerase chain reaction (RACE-PCR) to isolate three PDE5 isoforms from human corpus cavernosum. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis on eight human cavernous tissue samples showed that all samples expressed the PDE5A1 at a lower level than the PDE5A2 isoform. Five samples expressed the PDE5A3 isoform at various levels while the other three did not. Analysis on non-penile tissues showed that all tissues expressed the A1 and A2 isoforms while only those that have substantial amounts of smooth muscle expressed the A3 isoform. Cloning and sequencing of the PDE5A gene showed that the isoform-specific 5'-ends of the PDE5 mRNAs are encoded from three alternative first exons arranged in the order of A1-A3-A2. Promoter activities were detected upstream from the A1-specific exon and in the intron preceding the A2-specific exon. The upstream PDE5A promoter is expected to direct the expression of all three PDE5 isoforms while the intronic PDE5A2 promoter only the A2 isoform. Both promoters were upregulated by increasing concentrations of either cAMP or cGMP. Several transcription factor AP2 and Sp1-binding sequences identified in the promoters are likely to be the mediators of cAMP/cGMP-responsiveness.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Using a personal digital assistant to document clinical pharmacy services in an intensive care unit.

Management Case Studies describe approaches to real-life management problems in health systems. Each installment is a brief description of a problem and how it was dealt with. The cases are intended to help readers deal with similar experiences in their own work sites. Problem solving, not hypothesis testing, is emphasized. Successful resolution of the management issue is not a criterion for publication--important lessons can be learned from failures, too.

British Columbia↗
PubMed2001

Thrombin receptor signaling to cytoskeleton requires Hsp90.

Thrombin is a serine protease that evokes various cellular responses involved in injury and repair of the nervous system through the activation of protease-activated receptor-1 (PAR-1). Signals that modulate cell morphology precede most PAR-1 effects, but the initial signal transduction molecules are not known. Using the yeast two-hybrid system, we identified Hsp90, a chaperone with known signaling properties, as a binding partner of PAR-1. The interaction was confirmed by glutathione S-transferase pull-down, overlay, and co-immunoprecipitation assays. Morphological assays in mouse astrocytes were carried out to evaluate the importance of Hsp90 during cytoskeletal signaling. Reducing Hsp90 levels by antisense treatment or disruption of the Hsp90.PAR-1 complex by the Hsp90-specific drug geldanamycin attenuated thrombin-mediated astrocyte shape changes. Furthermore, overexpression of the PAR-1 cytoplasmic tail abrogated thrombin-induced cytoskeletal changes in neuronal cells. Treatment with geldanamycin specifically inhibited activation of RhoA without affecting thrombin-mediated intracellular calcium release, revealing the regulation of a distinct signaling pathway by Hsp90. Taken together, these studies demonstrate that Hsp90 may be essential for PAR-1-mediated signaling to the cytoskeleton.

Animals↗
PubMed2001

Conceptualizing quality of life for elderly people with stroke.

PURPOSE: Despite increased interest in quality of life (QOL) as an outcome measure and as a means of identifying client needs in health care, its conceptualisation and the identification of its constituents have been poorly researched for elderly people with stroke in Hong Kong. METHOD: This article analysed the literature to identify components relevant to the QOL of Chinese elderly people with stroke living in the community in Hong Kong. RESULTS: While common components of QOL for elderly people with and without stroke and regardless of cultural background were identified, a number were specific to an elderly Chinese stroke population. CONCLUSION: Recommendations for future research have been made with reference to further exploring and validating these components for the target population. A clear understanding of these aspects is essential for the development of sensitive QOL measures to guide and evaluate service delivery to this population.

Activities of Daily Living↗
PubMed2001

MDM2 and MDMX can interact differently with ARF and members of the p53 family.

Members of the p53 family of transcription factors have essential roles in tumor suppression and in development. MDM2 is an essential regulator of p53 that can inhibit the transcriptional activity of p53, shuttle p53 out of the nucleus, and target p53 for ubiquitination-mediated degradation. Little is known about the interaction and selectivity of different members of the p53 family (p53, p63, and p73) and the MDM2 family (MDM2 and MDMX). Here we show that the transcriptional activities of p53 and p73, but not that of p63, were inhibited by both MDM2 and MDMX. Consistent with these, we found that MDMX can physically interact with p53 and p73, but not with p63. Moreover, ectopically expressed MDM2 and MDMX could induce alterations in the subcellular localization of p73, but did not affect the subcellular localization of p53 and p63. Finally, we demonstrate that while ARF can interact with MDM2 and inhibit the regulation of p53 by MDM2, no interaction was found between ARF and MDMX. These data reveal that significant differences and selectivity exist between the regulation of different members of the p53 family by MDM2 and MDMX.

ADP-Ribosylation Factors↗
PubMed2001

Identification and regulation of human PDE5A gene promoter.

PDE5A gene encodes type 5 phosphodiesterase (PDE5), the principal cGMP-catalyzing enzyme in the penis and the primary target of sildenafil (Viagra). We have isolated a 3.7-kb DNA fragment that contains the human PDE5A gene promoter. The DNA fragment contains a sequence of 234 nucleotides at its 3' end that corresponds to most of the untranslated region of the PDE5A1 mRNA. The remaining 3.5-kb upstream flanking sequence contains no apparent TATA box but has several sequences that resemble binding sequences for transcription factors such as androgen receptor (AR), AP1, AP2, AP4, Sp1, MyoD, Myc, and CArG. In search of promoter activities, we used a luciferase reporter system to examine 10 DNA fragments that cover various regions of the 3.7-kb fragment. We found that a full basal promoter activity was confined to a 139-bp region that includes 78 bp of the PDE5A1-specific first exon. A lesser basal promoter activity was still detectable in a 94-bp fragment that contains the same 78-bp PDE5A1-specific exon plus 16 bp of upstream sequence. Either the 139-bp or the 94-bp promoter fragment responded minimally to cAMP or cGMP (2 mM) stimulation. Longer fragments that contain either a 308-bp 5' extension (from the 138-bp fragment) or a 156-bp 3' extension (all exon sequence) responded at higher levels to cAMP and cGMP stimulation. The 5' and 3' extensions cooperated with each other to provide the highest level of responses to cAMP and cGMP stimulation. DNase I footprint analysis identified four AP2- and two Sp1-binding sites in the 5' extension and four Sp1-binding sites in the 3' extensions. Cyclic AMP and cGMP had similar stimulatory effects on the PDE5A promoter.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Regulation of human PDE5A2 intronic promoter by cAMP and cGMP: identification of a critical Sp1-binding site.

PDE5A gene encodes type 5 phosphodiesterase (PDE5), the principal cGMP-catalyzing enzyme in the penis and the primary target of sildenafil (Viagra). We have previously reported the isolation of three alternatively spliced PDE5A isoforms in humans. We also reported the identification of three corresponding alternative first exons and an intronic promoter in the human PDE5A gene. The intronic promoter is situated upstream from the PDE5A2-specific first exon but downstream from the PDE5A1- and A3-specific first exons. In the current study we showed that the intronic promoter could be upregulated by either cAMP or cGMP. In order to identify possible regulatory elements in the promoter, we created deletion and base-substitution mutants targeting one AP2- and four Sp1-binding sequences. Loss of function of these mutants to bind to the respective transcription factors was verified by DNase I footprint analysis, and changes in promoter function were analyzed with a luciferase reporter system. Mutation of the AP2-binding sequence and deletion of the 3'-most Sp1-binding site (within the exon) had little effects on the basal or the cyclic nucleotide-inducible promoter functions. Mutation of the 5'-most Sp1-binding site had much more severe effects on the basal and the cyclic nucleotide-inducible promoter functions. Mutation of a neighboring site that contains two overlapping Sp1-binding sequences completely nullified the basal and cyclic nucleotide-inducible promoter activities. Thus, the PDE5A2 intronic promoter depends on the overlapping Sp1-binding site for basal and cyclic nucleotide-inducible functions.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Genetic imbalances in pT2 breast cancers of southern Chinese women.

While much information has been reported on the genetic alterations in breast cancers of Caucasians, little is known about the Oriental populations where breast cancers currently rank the second most common neoplasm. As a first step toward understanding the underlying genetics changes in this population, we used comparative genomic hybridization (CGH) to the genome-wide analysis of forty pT2 tumors from patients of a racially homogenous population in southern China. A complex pattern of genetic alterations emerged with the commonest chromosomal gains identified on 1q (58%), 8q (55%), 11q13 (25%), 16p (28%), 17q (53%) and 20q (35%), and frequent losses on 8p (38%), 11q (28%), 13q (30%) and 18q (25%). When breast cancers with and without lymph-node metastasis were compared, a higher copy gain of 10p was identified in the node-positive group (P=.036). An overall increase in the average number of genetic aberrations was also identified in the late onset group (>45 years)(P=.042) with a higher incidence of genetic losses noted (P=.035). In particular, losses on 16q were detected in 30% of the late onset patients but none in the early onsets (P=0.049). In this study, we have illustrated the pattern of genetic changes in breast tumors of southern Chinese females. While frequent 1q, 8q, 17q and 20q gains, and common 8p and 13q deletions detected were consistent to those aberrations reported from the Caucasian populations, the difference in genetic changes associated in lymph-node metastasis and age of onset identified should provide the basis for additional investigations into the underlying tumorigenesis in the Oriental population.

Adult↗
PubMed2001

Crystallizing thoughts about DNA base excision repair.

Chemically damaged bases are removed from DNA by glycosylases that locate the damage and cleave the bond between the modified base and the deoxyribose sugar of the DNA backbone. The detection of damaged bases in DNA poses two problems: (1) The aberrant bases are mostly buried within the double helix, and (2) a wide variety of chemically different modifications must be efficiently recognized and removed. The human alkyladenine glycosylase (AAG) and Escherichia coli Alka DNA glycosylases excise many different types of alkylated bases from DNA. Crystal structures of these enzymes show how substrate bases are exposed to the enzyme active site and they suggest mechanisms of catalytic specificity. Both enzymes bend DNA and flip substrate bases out of the double helix and into the enzyme active site for cleavage. Although AAG and AlkA have very different overall folds, some common features of their substrate-binding sites suggest related strategies for the selective recognition of a chemically diverse group of alkylated substrates.

Alkylation↗
PubMed2001

Decreased trabecular smooth muscle and caveolin-1 expression in the penile tissue of aged rats.

PURPOSE: Because decreased trabecular smooth muscle content is reportedly associated with vasculogenic impotence in men, we performed a rodent study to investigate the effect of aging on trabecular smooth muscle content and caveolin-1 protein expression in penile smooth muscle cells. MATERIALS AND METHODS: In 6 young (age 3 months) and 6 old (age 24 months) rats erectile function was evaluated by cavernous nerve stimulation. At sacrifice penile tissue samples were collected for Western blot analysis, Masson's trichrome staining, caveolin-1 immunostaining and electron microscopy. The percent of smooth muscle in the trabecular tissue was assessed by computer assisted image analysis. RESULTS: In the aged rats mean intracavernous pressure plus or minus standard deviation was decreased (70 +/- 8.8 versus 107 +/- 12.3 cm. water) and the latency period was increased (7.8 +/- 1.2 versus 4.5 +/- 0.5 seconds) significantly compared to values in the young rats (p <0.001). The mean ratio of trabecular smooth muscle-to-connective tissue was also significantly altered in old versus young rats (27% +/- 2.9% versus 42.1% +/- 5.1%, p <0.001). Immunostaining for caveolin-1 was noted in each group in the sarcolemma of smooth muscle cells and endothelium of trabecular sinusoids but the staining pattern was less intense and the percent of smooth muscle positive for caveolin-1 was decreased in aged versus young rats (17.9% +/- 2.5% versus 27.5% +/- 3.6%, p <0.001). Moreover, young trabecular smooth muscle cells had more caveolae in the sarcolemma on electron microscopy and a higher expression of caveolin-1 protein on Western blot analysis. In contrast, higher endothelial nitric oxide synthase protein expression was noted in the penile tissue of old rats. CONCLUSIONS: In these aged rats the decreased ratio of trabecular smooth muscle-to-collagen and the reduced expression of caveolin-1 may contribute to erectile dysfunction.

Aging↗
PubMed2000

During ontogeny primitive (CD34(+)CD38(-)) hematopoietic cells show altered expression of a subset of genes associated with early cytokine and differentiation responses of their adult counterparts.

Comparison of gene expression profiles in closely related subpopulations of primitive hematopoietic cells offers a powerful first step to elucidating the molecular basis of their different biologic properties. Here we present the results of a comparative quantitative analysis of transcript levels for various growth factor receptors, ligands, and transcription factor genes in CD34(+)CD38(-) and CD34(+)CD38(+) cells purified from first trimester human fetal liver, cord blood, and adult bone marrow (BM). In addition, adult BM CD34(+)CD38(-) cells were examined after short-term exposure to various growth factors in vitro. Transcripts for 19 of the 24 genes analyzed were detected in unmanipulated adult BM CD34(+)CD38(-) cells. Moreover, the levels of transforming growth factor beta (TGF-beta), gp130, c-fos, and c-jun transcripts in these cells were consistently and significantly different (higher) than in all other populations analyzed, including phenotypically similar but biologically different cells from fetal or neonatal sources, as well as adult BM CD34(+) cells still in G(0) after 2 days of growth factor stimulation. We have thus identified a subset of early response genes whose expression in primitive human hematopoietic cells is differently regulated during ontogeny and in a fashion that is recapitulated in growth factor-stimulated adult BM CD34(+)CD38(-) cells, before their cell cycle progression and independent of their subsequent differentiation response. These findings suggest a progressive alteration in the physiology of primitive hematopoietic cells during development such that these cells initially display a partially "activated" state, which is not maximally repressed until after birth. (Blood. 2000;96:4160-4168)

ADP-ribosyl Cyclase↗