Biomedical subjects

C Cheung

Publications and source records attributed to C Cheung.

At least 19 recordsLinked to original sources

PubMed2006

Alterations in transporter expression in liver, kidney, and duodenum after targeted disruption of the transcription factor HNF1alpha.

The transcription factor hepatocyte nuclear factor 1alpha (HNF1alpha) is involved in regulation of glucose metabolism and transport, and in the expression of several drug and bile acid metabolizing enzymes. Targeted disruption of the HNF1alpha gene results in decreased Cyp1a2, and Cyp2e1 expression, and increased Cyp4a1 and Cyp7a1 expression, suggesting these enzymes are HNF1alpha target genes. Since hepatic metabolism can be coordinately linked with drug and metabolite transport, this study aims to demonstrate whether HNF1alpha regulates expression of a variety of organic anion and cation transporters through utilization of an HNF1alpha-null mouse model. Expression of 32 transporters, including members of the Oat, Oatp, Oct, Mrp, Mdr, bile acid and sterolin families, was quantified in three different tissues: liver, kidney, and duodenum. The expression of 17 of 32 transporters was altered in liver, 21 of 32 in kidney, and 6 of 32 in duodenum of HNF1alpha-null mice. This includes many novel observations, including marked downregulation of Oats in kidney, as well as upregulation of many Mrp and Mdr family members in all three tissues. These data indicate that disruption of HNF1alpha causes a marked attenuation of several Oat and Oatp uptake transporters in liver and kidney, and increased expression of efflux transporters such as Mdrs and Mrps, thus suggesting that HNF1alpha is a central mediator in regulating hepatic, renal, and intestinal transporters.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Antidermatophyte activity of medicago extracts and contained saponins and their structure-activity relationships.

Saponin-rich extracts of Medicago sativa L. have been shown to display antifungal activity against a range of common fungibut only a few individual saponins have been tested against dermatophytes. Total saponins were separately obtained from roots and aerial parts of Medicago sativa, M. murex, M. arabica and M. hybrida. Nineteen saponins and three parent triterpenoids, were tested against three dermatophytic fungi Microsporum gypseum, Trichophyton interdigitale and T. tonsurans using mircowell plate serial dilution assay to determine the Minimum Inhibitory Concentration (MIC). Miconazole was used as a positive control. T. tonsurans appeared to be the most sensitive of the dermatophytes to the active compounds. Aglycones showed less antifungal effect than the glycosides, which displayed a range of activities. Monodesmosidic glycosides of medicagenic acid were the most active compounds, especially the 3-O-beta-D-glucopyranoside, which displayed MIC less than 0.09mm against all three fungi, although those of hederagenin and zanhic acid also showed weak activity (MIC 3.3mm against two fungal species). Bidesmosidic saponins had weaker activity than monodesmosidic ones. This corresponds to activity of these and similar compounds against other fungal species but this is the first comprehensive report of activity of Medicago saponins against dermatophytes.

Antifungal Agents↗

PubMed2006

Development of candidemia on caspofungin therapy: a case report.

Caspofungin, an echinocandin, is approved for use in invasive candidiasis. Few cases of break-through candidal infections during caspofungin therapy have been reported and none have involved Candida parapsilosis. Here, we report a patient who developed multiple post-operative complications after pancreaticoduodenectomy for a pancreatic mass, including fungemia due to C. parapsilosis, while on caspofungin for treatment of Candida glabrata peritonitis. The fungemia resolved after a central venous catheter was removed and therapy was switched from caspofungin to amphotericin B lipid complex. Studies of C. parapsilosis susceptibility and the pharmacodynamics and drug interactions of caspofungin that may contribute to breakthrough fungemia are discussed.

Aged↗

PubMed2005

Severe acute renal failure in adults: place of care, incidence and outcomes.

BACKGROUND: Department of Health guidelines recommend specialist critical care facilities for patients with severe single-organ failure such as acute renal failure (ARF). Prospective studies examining incidence, causes and outcomes of ARF outside of intensive care settings are lacking. AIM: To determine the incidence, causes, place of care and outcomes of severe single-organ ARF. DESIGN: Prospective observational study. METHODS: For 6 weeks in June-July 2003, renal physicians were contacted daily, and ICUs on alternate days, to identify cases of severe single-organ ARF in the Greater Manchester area. All patients with serum creatinine >or=500 micromol/l and not requiring other organ support were included. Patients with end-stage renal disease were excluded. Survivors were followed up at 90 days and 1 year from admission. Two independent consultant nephrologists assessed each case using anonymized summaries. RESULTS: Eighty-five patients had multi-organ ARF and 28 had severe single-organ ARF (380 and 125 pmp/year, respectively). Of those with single-organ ARF, 10 (36%) had known pre-existing chronic kidney disease. Renal replacement therapy (RRT) was required in 15 (54%). Total bed occupancy on ICUs relating to single-organ ARF was 59 days (range per patient 1-21). At 90 days, 18 (64%) were alive, and 17 (94%) had independent renal function. At 1 year, 4/18 had died, none receiving RRT at the time of death. Survivors all had independent renal function. In 13 (46%) cases there was an unacceptable delay in patient transfer and in 7 (25%), delays in assessment or commencement of RRT may have adversely affected patient outcome. DISCUSSION: The incidence of ARF treated with RRT is rising. Delays in transfer to renal services may result in inappropriate ICU bed use, and may adversely affect patient outcomes. There are serious problems regarding the appropriate use of expensive and limited medical resources in the critical care area, and in providing safe and effective treatment of patients with ARF.

Acute Kidney Injury↗

PubMed2005

'Smart' delivery systems for biomolecular therapeutics.

OBJECTIVE: There is a strong need for drug delivery systems that can deliver biological signals from biomaterials and tissue engineering scaffolds, and a particular need for new delivery systems that can efficiently deliver biomolecules to intracellular targets. Viruses and pathogens have evolved potent molecular machinery that sense the lowered pH gradient of the endosomal compartment and become activated to destabilize the endosomal membrane, thereby enhancing protein or DNA transport to the cytoplasmic compartment. A key feature of many of these biological delivery systems is that they are reversible, so that the delivery systems are not directly toxic. These delivery systems have the ability to change their structural and functional properties and thus display remarkable 'smart' material properties. The objective of this presentation is to review the initial development of smart polymeric carriers that mimic these biological delivery systems and combine similar pH-sensitive, membrane-destabilizing activity for the delivery of therapeutic biomolecules. DESIGN: We have developed new 'smart' polymeric carriers to more effectively deliver and broaden the available types of biomolecular therapeutics. The polymers are hydrophilic and stealth-like at physiological pH, but become membrane-destabilizing after uptake into the endosomal compartment where they enhance the release of therapeutic cargo into the cytoplasm. They can be designed to provide a range of pH profiles and membrane-destabilizing activities, allowing their molecular properties to be matched to specific drugs and loading ranges. A versatile set of linker chemistries is available to provide degradable conjugation sites for proteins, nucleic acids, and/or targeting moieties. RESULTS: The physical properties of several pH-responsive polymers were examined. The activity and pH profile can be manipulated by controlling the length of hydrophobic alkyl segments. The delivery of poly(propyl acrylic acid) (PPAA)-containing lipoplexes significantly enhanced wound healing through the interconnected effects of altered extracellular matrix organization and greater vascularization. PPAA has also been shown to enhance cytoplasmic delivery of a model protein therapeutic. Polymeric carriers displaying pH-sensitive, membrane-destabilizing activity were also examined. The pH profile is controlled by the choice of the alkylacrylic acid monomer and by the ratio of the carboxylate-containing alkylacrylic acid monomer to alkylacrylate monomer. The membrane destabilizing activity is controlled by the lengths of the alkyl segment on the alkylacrylic acid monomer and the alkylacrylate monomer, as well as by their ratio in the final polymer chains. CONCLUSION: The molecular mechanisms that proteins use to sense and destabilize provide interesting paradigms for the development of new polymeric delivery systems that mimic biological strategies for promoting the intracellular delivery of biomolecular drugs. The key feature of these polymers is their ability to directly enhance the intracellular delivery of proteins and DNA, by destabilizing biological membranes in response to vesicular compartment pH changes. The ability to deliver a wide variety of protein and nucleic acid drugs to intracellular compartments from tissue engineering and regenerative scaffolds could greatly enhance control of important processes such as inflammation, angiogenesis, and biomineralization.

Biocompatible Materials↗

PubMed2003

Brain morphological abnormality in schizophrenia is independent of country of origin.

OBJECTIVE: The disorder schizophrenia has a worldwide prevalence of 1% and is generally associated with lateral cerebral ventricular enlargement. Whether there is a relationship between these two findings is unclear but has aetiological relevance. METHOD: Consecutively admitted Chinese patients (n = 19) with first episode of schizophrenia and healthy community volunteers (n = 29) underwent magnetic resonance imaging brain scan. The groups were balanced for age, sex, best social class and handedness. These patients were similar on clinical and socio-demographic indices to those who declined participation (n = 15). Semi-automated volumetric analysis of whole brain volume, cortical grey matter, cerebrospinal fluid, sulci and lateral ventricles was performed. RESULTS: Chinese patients in their first episode of schizophrenia have significant enlargement of lateral ventricles. CONCLUSION: Brain morphological abnormality in schizophrenia is present regardless of the country of origin. The importance of genes in driving normal brain development and stable prevalence suggests that aetiology may favour genes over environment.

Adult↗

PubMed2001

High-performance liquid chromatography method for the quantification of non-radiolabelled cinnamic compounds in analytes derived from human skin absorption and metabolism experiments.

An isocratic high-performance liquid chromatography method has been developed for the quantification of the skin sensitisers trans-cinnamaldehyde and trans-cinnamic alcohol, and their cinnamic metabolites. The relative standard deviations (RSDs) between the gradients of eight sets of standard curves were 2.8, 3.1 and 1.9% for cinnamic alcohol, cinnamaldehyde and cinnamic acid, respectively. Sample analytes were derived from two series of experiments: in vitro full-thickness human skin absorption and metabolism studies and metabolism studies using human skin homogenates, with non-radiolabelled cinnamic compounds. Skin absorption and metabolism experiments were performed in the absence and presence of the alcohol dehydrogenase inhibitor, pyrazole. Samples from full-thickness skin absorption studies were analysed without extraction; cinnamic compounds from within skin were extracted into methanolic solutions using newly developed methods. The intra-assay RSDs ranged from 0.17 to 2.52% for cinnamic alcohol, 0.24 to 9.14% for cinnamaldehyde and 0.26 to 6.43% for cinnamic acid. The inter-assay RSDs for cinnamic alcohol, cinnamaldehyde and cinnamic acid, respectively, as determined from n=20 HPLC runs, were 2.10, 4.16 and 2.26%.

Acrolein↗

PubMed2001

Medical informatics--the state of the art in the Hospital Authority.

Since its inception in 1990, the Hospital Authority (HA) has strongly supported the development and implementation of information systems both to improve the delivery of care and to make better information available to managers. This paper summarizes the progress to date and discusses current and future developments. Following the first two phases of the HA information technology strategy the basic infrastructural elements were laid in place. These included the foundation administrative and financial systems and databases; establishment of a wide area network linking all hospitals and clinics together; laboratory, radiology and pharmacy systems with access to results in the ward. A major push into clinical systems began in 1994 with the clinical management system (CMS), which established a clinical workstation for use in both ward and ambulatory settings. The CMS is now running at all major hospitals, and provides single logon access to almost all the electronically collected clinical data in the HA. The next phase of development is focussed on further support for clinical activities in the CMS. Key elements include the longitudinal electronic patient record (ePR), clinical order entry, generic support for clinical reports, broadening the scope to include allied health and the rehabilitative phase, clinical decision support, an improved clinical documentation framework, sharing of clinical information with other health care providers and a comprehensive data repository for analysis and reporting purposes.

China↗

PubMed2001

In vivo cerebrovascular measurement combining diffuse near-infrared absorption and correlation spectroscopies.

We combine two near-infrared diffuse optical techniques to study variations of blood flow, haemoglobin concentration, and blood oxygen saturation in the functioning rat brain. Diffuse correlation spectroscopy (or flowmetry) monitors changes in the cerebral blood flow, without the use of the principles of tracer clearance, by measuring the optical phase-shifts caused by moving blood cells. Near-infrared absorption spectroscopy concurrently measures tissue absorption at two wavelengths to determine haemoglobin concentration and blood oxygen saturation in this same tissue volume. This optical probe is non-invasive and was employed through the intact skull. The utility of the technique is demonstrated in vivo by measuring the temporal changes in the regional vascular dynamics of rat brain during hypercapnia. Temporal and spatial variations of cerebral blood flow, haemoglobin concentration and blood oxygen saturation during hypercapnia are compared with other measurements in the literature, and a quantitative analysis demonstrating the self-consistency of our combined observations of vascular response is presented.

Animals↗

PubMed2001

Human adipose tissue endothelial cells promote preadipocyte proliferation.

Adipogenesis is preceded by development of a microvascular network, and optimal functioning of adipose tissue as an energy store and endocrine organ is dependent on extensive vascularization. We have examined the role of endothelial cell-derived factors that influence the proliferation of human preadipocytes. Microvascular endothelial cells and preadipocytes were isolated from human omental and subcutaneous adipose tissue biopsies by use of a developed procedure of collagenase digest, immunoselection, and differential trypsinization. Conditioned medium from microvascular endothelial cell cultures promoted the proliferation of preadipocytes (P = <0.001) and (to a lesser extent) other cell types. No depot-specific differences in mitogenic capacity of microvascular endothelial cell medium or of preadipocyte response were observed. These results indicate that adipose tissue endothelial cells secrete soluble adipogenic factor(s).

Adipocytes↗

PubMed2001

Comparison of radiological severity in psoriatic arthritis and rheumatoid arthritis.

OBJECTIVE: To compare the radiological severity of patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). METHODS: Patients were identified from the University of Toronto PsA and RA databases. Using the earliest available radiographs, each RA patient was matched to a single PsA patient on the basis of sex, age, and disease duration. Two rheumatologists blinded to the patient's diagnosis scored the radiographs using the modified Steinbrocker method. RESULTS: PsA and RA groups were similar with respect to demographics as well as the use of disease modifying antirheumatic medications. No significant difference in Steinbrocker score for the hands and feet or the hands only was noted. Patients with RA had a higher radiological score in the feet. The 2 groups were similar in the number of joints with significant radiological damage (Steinbrocker 3 and 4). CONCLUSION; Overall the radiological severity in the hands and feet of patients with PsA was comparable to that of patients with RA.

Adult↗

PubMed2000

Founder's Award, Society for Biomaterials. Sixth World Biomaterials Congress 2000, Kamuela, HI,May 15-20, 2000. Really smart bioconjugates of smart polymers and receptor proteins.

Over the past 18 years we have been deeply involved with the synthesis and applications of stimuli-responsive polymer systems, especially polymer-biomolecule conjugates. This article summarizes our work with one of these conjugate systems, specifically polymer-protein conjugates. We include conjugates prepared by random polymer conjugation to lysine amino groups, and also those prepared by site-specific conjugation of the polymer to specific amino acid sites that are genetically engineered into the known amino acid sequence of the protein. We describe the preparation and properties of thermally sensitive random conjugates to enzymes and several affinity recognition proteins. We have also prepared site-specific conjugates to streptavidin with temperature-sensitive polymers, pH-sensitive polymers, and light-sensitive polymers. The preparation of these conjugates and their many fascinating applications are reviewed in this article.

Acrylamides↗

PubMed2000

Molecular engineering of proteins and polymers for targeting and intracellular delivery of therapeutics.

There are many protein and DNA based therapeutics under development in the biotechnology and pharmaceutical industries. Key delivery challenges remain before many of these biomolecular therapeutics reach the clinic. Two important barriers are the effective targeting of drugs to specific tissues and cells and the subsequent intracellular delivery to appropriate cellular compartments. In this review, we summarize protein engineering work aimed at improving the stability and refolding efficiency of antibody fragments used in targeting, and at constructing new streptavidin variants which may offer improved performance in pre-targeting delivery strategies. In addition, we review recent work with pH-responsive polymers that mimic the membrane disruptive properties of viruses and toxins. These polymers could serve as alternatives to fusogenic peptides in gene therapy formulations and to enhance the intracellular delivery of protein therapeutics that function in the cytoplasm.

Antibodies↗

PubMed1999

Expression and localization of human alcohol and aldehyde dehydrogenase enzymes in skin.

Alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase (ALDH; EC 1.2.1.3.) are important enzymes involved in the biotransformation of both alcohols and aldehydes. Today, six classes of ADH and twelve classes of ALDH have been defined in mammals. Here we report the detection and localisation of three classes of ADH and two classes of ALDH in human skin, using Western blot analysis and immunohistochemistry with class-specific antisera. Western blot analysis of human skin cytosol revealed that class I-III ADH and class 1 and class 3 ALDH enzymes are expressed, constitutively, in three different anatomical regions of human skin (foreskin, breast, abdomen). Densitometric analysis of the immunoreactive bands revealed differential constitutive expression of these enzymes in foreskin, breast, and abdomen skin. Immunohistochemistry showed the presence of class I ADH and class III ADH enzymes, predominantly in the epidermis with some localised expression in the dermal appendages of human skin. In comparison, staining for class II ADH was more faint in the epidermis with very little dermal expression. Class 1 ALDH and class 3 ALDH were predominantly localised to the epidermis with minimal, highly localised dermal appendageal expression. These cutaneous ADH and ALDH enzymes may play significant roles in the metabolism of endogenous or xenobiotic alcohols and aldehydes.

Adolescent↗

PubMed1999

HLA-C locus alleles in patients with psoriatic arthritis (PsA).

The aim of this investigation was to compare the frequency of alleles at the HLA-C locus in patients with psoriatic arthritis to that in the disease free population and to relate the HLA genes to disease phenotype in psoriatic arthritis (PsA). Ninety-four consecutive patients seen in the (PsA) clinic between April and July 1996 and 100 disease-free controls had HLA typing performed by both serologic and molecular techniques. Patients' disease was assessed according to a standard protocol. Fisher's exact test was used to compare the frequency of HLA alleles in the patients and controls. HLA-C determined by PCR-SSP decreased the frequency of non-identified, that is, "blank" (or null) alleles to 6% in patients and controls. HLA-Cw*0602 was present in 32 patients and 18 controls: allele frequency of 17% in the patients versus 9% in the controls (p < 0.01). Amongst patients with psoriatic arthritis, those who carried the HLA-Cw*0602 allele had a significantly earlier mean age of onset of their psoriasis (p = 0.003). This study confirms that molecular DNA techniques improve detection of C-locus alleles. The HLA-Cw*0602 is increased amongst patients with psoriatic arthritis compared to controls. The HLA-Cw*0602 is associated with an earlier age of onset of psoriasis.

Age of Onset↗

PubMed1999

Apoptosis and expression of cytotoxic T lymphocyte effector molecules in renal allografts.

Cytotoxic T lymphocyte (CTL) mediated apoptosis is thought to play a major role in the rejection of renal allografts following transplantation, however, the CTL effector mechanism that is primarily responsible for immunological rejection is unknown. The two major effector pathways of CTL killing which lead to apoptosis involve the Fas/Fas ligand (Fas L) lytic pathway, and the perforin/granzyme degranulation pathway. The expression of CTL effector molecules which influence these pathways include Fas, Fas L and TiA-1 (cytotoxic granule protein). This study has investigated apoptosis by in situ terminal deoxytransferase-catalysed DNA nick end labelling (TUNEL), and the expression of CTL effector molecules by immunohistochemistry, in renal allograft biopsies obtained from patients following kidney transplantation. Renal biopsies were classified into three histological groups; acute cellular rejection, chronic rejection, or no rejection. The extent of T-cell infiltration of renal tissues was assessed by immunohistochemical staining with an anti-CD3 monoclonal antibody. Numerous TUNEL positive cells were detected in all transplant biopsies examined; these consisted mainly of renal tubular cells and infiltrating cells, with some TUNEL positive cells also detected in the glomeruli. In the case of normal kidney tissue, renal cells also stained positive for TUNEL but there was no lymphocytic infiltration. There was significantly more T-cell infiltration observed in acute rejection biopsies compared to the no rejection biopsies. In the case of Fas L expression, there was little expression in all three biopsy groups, apart from one case of chronic rejection. Conversely, although there were no significant differences in TiA-1 expression between the three biopsy groups, TiA-1 expression was more prominent in acute rejection biopsies. Furthermore, Fas expression was significantly decreased in acute rejection biopsies when compared to those of chronic and no rejection in which Fas was predominantly localized in the renal tubular cells. These results indicate that the mechanism of CTL killing leading to the rejection of renal allografts may be different in acute and chronic rejection. Moreover, our data indicate the potential for cytotoxic granule-based CTL killing in acute renal allograft rejection but not in chronic rejection.

Adult↗

PubMed1999

Expression of apoptotic regulatory molecules in renal cell carcinoma: elevated expression of Fas ligand.

Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO-1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.

Adult↗

PubMed1999

A variant of pyothorax-associated lymphoma.

A case of pleural lymphoma that developed after an episode of empyema is described. This may be a variant presentation of the rare yet distinct condition termed pyothorax-associated lymphoma. This condition was first recognised in Japan; there have been only a few reports in Western countries to date. A feature of this case is the relatively short interval between diagnosis of empyema and subsequent development of lymphoma.

Aged↗