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Biomedical subjects

M Cheung

Publications and source records attributed to M Cheung.

At least 19 recordsLinked to original sources
PubMed2006

Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning.

Remote ischemic preconditioning reduces myocardial infarction (MI) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K(+)-dependent ATP (K(ATP)) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 +/- 14.3 vs. 38.3 +/- 15.4%, P = 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion (P = 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 +/- 6% and 3 +/- 5% in control and PerC, respectively (P = 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group (P = 0.04). There were fewer malignant arrhythmias with PerC during reperfusion (P = 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a K(ATP) channel-dependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes.

Adenosine Triphosphate↗
PubMed2004

Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models.

During the development of indazolylpyrimidines as novel and potent inhibitors of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) tyrosine kinase, we observed that some human tumour xenografts are more sensitive to VEGFR2 kinase inhibitors than others. A better understanding of the basis for this differential response may help to identify a predictive marker that would greatly aid in the identification of a suitable patient population for treatment. One representative compound from the indazolylpyrimidine series is GW654652 that inhibited all three VEGFRs with similar potency. The inhibition of VEGFR2 kinase by GW654652 was about 150 to >8800 more potent than the inhibition of eight other kinases tested. GW654652 inhibited VEGF- and bFGF-induced proliferation in endothelial cells with an IC(50) of 110 and 1980 nM, respectively, and has good pharmacokinetic profile in mouse and dog. We investigated the association between VEGF and VEGFR2 expression and the antitumour efficacy of GW654652, in various xenograft models. Statistically significant associations were observed between the antitumour efficacy of GW654652 in xenografts and VEGF protein (P=0.005) and VEGFR2 expression (P=0.041). The oral dose of GW654652 producing 50% inhibition of tumour growth (ED(50)) decreased with increasing levels of VEGF (r=-0.94); and, in contrast, the ED(50) increased with the increased expression of VEGFR2 (r=0.82). These results are consistent with the observed inverse correlation between VEGF and VEGFR2 expression in tumours. These findings support the hypothesis that VEGF and VEGFR2 expression by tumours may predict the therapeutic outcome of VEGFR kinase inhibitors.

Animals↗
PubMed2004

Right thoracic paravertebral analgesia for hepatectomy.

Haemostatic deficiencies, common among cirrhotic patients, may deteriorate further after hepatectomy, increasing the bleeding risk associated with the use of thoracic epidural analgesia. We describe two patients who enjoyed immediate post-operative tracheal extubation and satisfactory analgesia using mainly right thoracic paravertebral analgesia after right lobe hepatectomy.

Analgesia, Epidural↗
PubMed2002

Optimization of electroporation conditions for Mycobacterium avium.

Successful transformation and subsequent genetic manipulation of Mycobacterium avium requires suitable vectors, efficient transformation systems, and reliable selectable markers. A systematic analysis of the parameters involved in the transformation of M. avium was performed to optimize DNA transfer. Factors examined included the composition of the growth medium, growth medium additives, variations in washing of the bacteria prior to electroporation, and conditions of electroporation. Of the parameters assayed, the frequency of transformation (defined as the number of transformants per 10(6) transformed bacteria) showed the greatest increase with the addition of 1.5% glycine to the M. avium culture medium and the use of higher concentrations of plasmid DNA. The addition of 0.5 M sucrose to the growth medium and wash solution yielded a modest increase in transformation frequency, but more importantly afforded greater consistency of results between different batches of cells with no decrease in transformation yields following freezing and thawing. We also confirmed that gfp could be used as a selective marker for M. avium, even as a single copy integrant, and allowed for rapid discrimination between false and true transformants. Using this protocol, we were able to transform nine of 11 clinical strains of M. avium.

Culture Media↗
PubMed2001

cSox3 expression and neurogenesis in the epibranchial placodes.

Epibranchial placodes are local thickenings of the surface ectoderm, which give rise to sensory neurons of the distal cranial ganglia. The development of these placodes has remained unclear due to the lack of any definitive marker for these structures. We show here that the chick transcription factor, cSox3, is expressed in four lateral patches at the rostral edge of the epibranchial arches and that these mark the epibranchial placodes. These patches of cSox3 expression arise by gradual thinning from broader areas of cSox3 expression with concomitant loss of cSox3 in nonplacodal regions. Cells leaving the epithelial placodes as they initiate neurogenesis, lose cSox3 expression and sequentially express Ngn1, NeuroD, NeuroM, and Phox2a, but do not express Ngn2. This is in contrast to studies in the mouse where it is Ngn2, rather than Ngn1, that is predominantly expressed in epibranchial-derived neuroblasts. Overexpression of cSox3 interferes with normal neuroblast migration and results in changes in ectodermal morphology. Thus, cSox3 provides a useful tool for the study of placode formation, and loss of cSox3 expression appears to be a necessary event in normal neurogenesis from the epibranchial placodes.

Animals↗
PubMed2001

Electron-beam tomography coronary calcium scores are superior to Framingham risk variables for predicting the measured proximal stenosis burden.

Previous studies of electron-beam tomography (EBT) have correlated coronary calcium scores with simplistic visual estimates of disease severity. In a clinical trial designed to evaluate 2 treatment strategies in coronary artery disease (CAD) patients with low levels of high-density lipoprotein cholesterol, we used quantitative coronary angiography to measure composite proximal stenosis burden from the baseline coronary angiogram and assessed the traditional Framingham risk variables in 146 patients. Stenosis burden is the sum, per patient, of percent stenosis for the worst lesion found in each of 9 standard proximal coronary segments. EBT estimates of coronary calcium (Agatston score, calcium volume score) were obtained for 115 of these patients. Stenosis burden was correlated with the calcium scores and risk variables. The best traditional correlates of stenosis burden were smoking status (r = 0.31, p = 0.001), prior myocardial infarction (r = 0.24, p = 0.005), body mass index (r = 0.23, p = 0.005), pack-years smoking (r = 0.20, p = 0.05), and age (r = 0.17, p = 0.04). With adjustment for age, all these correlations improved (eg, body mass index x age [r = 0.28, p = 0.001]). In addition, total cholesterol x age (r = 0.22, p = 0.008), fibrinogen x age (r = 0.19, p = 0.03), and systolic blood pressure x age (r = 0.18, p = 0.03) became significant correlates. Spearman correlations of the calcium scores with stenosis burden were considerably greater (Agatston: r = 0.62, p <0.0001; calcium volume: r = 0.63, p <0.0001). In multivariate regression analysis, calcium score, body mass index, and history of myocardial infarction were independent correlates of stenosis burden (R(2) = 0.45). At a given point in time, the EBT coronary calcium scores are greatly superior to the Framingham risk factors in predicting the measured proximal stenosis burden. Agatston and calcium volume scores are comparably predictive of stenosis burden.

Body Burden↗
PubMed2001

Comparison of the lipoprotein, carbohydrate, and hemostatic effects of phasic oral contraceptives containing desogestrel or levonorgestrel.

Desogestrel (DSG) is a less-androgenic progestogen than levonorgestrel (LNG). This difference in androgenicity may be responsible for observed differences in metabolic effects between oral contraceptive (OC) formulations containing almost equivalent estrogen doses but with either DSG or LNG as a progestogen. To test the hypothesis, a prospective 9-month randomized comparison of plasma lipids, glucose, insulin, hemostasis, and sex hormone binding globulin (SHBG) was conducted in 66 healthy women using phasic formulations of OCs containing either DSG (DSG-OC) or LNG (LNG-OC). The study results showed that SHBG increased 3-fold with DSG-OC and 2-fold with LNG-OC. DSG-OC increased HDL-C, HDL(2)-C and HDL(3)-C; LDL-C decreased transiently. LNG-OC decreased HDL(2)-C and increased HDL(3)-C; HDL-C was unchanged and LDL-C decreased transiently. Both formulations increased VLDL-C and triglycerides, more with DSG-OC, but apolipoprotein B levels increased equally. Apo A-I and A-II increased more with DSG-OC than with LNG-OC. Neither formulation altered Lp(a) or fasting glucose and insulin levels. Postprandially, both formulations decreased glucose and increased insulin responses, but to an equivalent degree. Both OCs slightly enhanced procoagulant and profibrinolytic parameters to the same extent except for internally compensating decreases in Factor V and protein S with DSG-OC. In summary, at almost equivalent estrogen doses, a phasic OC containing DSG compared with LNG has a less androgenic effect on lipoproteins and SHBG, similar effects on hemostatic parameters with lower protein S and factor V activity and equivalent effects on carbohydrate metabolism. The lipoprotein, SHBG, and protein S and factor V differences are likely due to the lesser androgenicity of DSG allowing for a greater expression of the dose of estrogen.

Adult↗
PubMed2001

Mercurial sensitivity of aquaporin 1 endofacial loop B residues.

The water channel protein aquaporin-1 (AQP1) has two asparagine-proline-alanine (NPA) repeats on loops B and E. From recent structural information, these loops are on opposite sides of the membrane and meet to form a pore. We replaced the mercury-sensitive residue cysteine 189 in AQP1 by serine to obtain a mercury-insensitive template (C189S). Subsequently, we substituted three consecutive cysteines for residues 71-73 near the first NPA repeat (76-78) in intracellular loop B, and investigated whether they were accessible to extracellular mercurials. AQP1 and its mutants were expressed in Xenopus laevis oocytes, and the osmotic permeability (P(f)) of the oocytes was determined. C189S had wild-type P(f) but was not sensitive to HgCl(2). Expression of all three C189S cysteine mutants resulted in increased P(f), and all three mutants regained mercurial sensitivity. These results, especially the inhibitions by the large mercurial p-chloromercunbenzene-sulfonic acid (pCMBS) ( approximately 6A wide), suggest that residues 71-73 at the pore are accessible to extracellular mercurials. A 30-ps molecular dynamics simulation (at 300 K) starting with crystallographic coordinates of AQP1 showed that the width of the pore bottleneck (between Connolly surfaces) can vary (w(avg) = 3.9 A, sigma = 0.75; hydrated AQP1). Thus, although the pore width would be > or = 6 A only for 0.0026 of the time, this might suffice for pCMBS to reach residues 71-73. Alternative explanations such as passage of pCMBS across the AQP1 tetramer center or other unspecified transmembrane pathways cannot be excluded.

Amino Acid Motifs↗
PubMed2000

Chick sox10, a transcription factor expressed in both early neural crest cells and central nervous system.

Human SOX10 and mouse Sox10 have been cloned and shown to be expressed in the neural crest derivatives that contribute to formation of the peripheral nervous system during embryogenesis. Mutations in Sox10 have been identified as a cause of the Dominant megacolon mouse and Waardenburg-Shah syndrome in human, both of which include defects in the enteric nervous system and pigmentation (and in the latter, sometimes hearing). We have cloned a chick Sox10 ortholog (cSox10) in order to study its role in neural crest cell development. This cDNA reveals a 1383 bp open reading frame encoding 461 amino acids which is highly conserved with human SOX10 and mouse Sox10. In situ hybridization showed cSox10 is expressed in migrating neural crest cells just after the zinc finger transcription factor Slug, but is lost as cells undergo neuronal differentiation in ganglia of the peripheral nervous system. In addition, cSox10 is expressed in the developing otic vesicle, the developing central nervous system and pineal gland.

Animals↗
PubMed2000

Roles of Sox4 in central nervous system development.

The transcription factor-encoding gene, Sox4, is expressed in a wide range of tissues and has been shown to be functionally involved in heart, B-cell and reproductive system development. Sox4 shows a high degree of sequence homology with another group C Sox gene, Sox11, which is predominantly expressed in the CNS. Since the expression of Sox4 in the CNS has not been described we have carried out such a study. Sox4 and Sox11 expression increased simultaneously in the same early differentiating cells of the developing CNS except in the external granule layer of the cerebellum where Sox11 expression preceded that of Sox4. As development proceeded, their expression always appeared to relate to the maturational stage of the cell population, with Sox11 expression more transient than Sox4, except in the spinal cord where the reverse was true. Sox4 knock-out mice have been shown to die of a heart defect half way through gestation with no observable CNS phenotype. Our more detailed analysis showed no abnormality in the spatial restriction of expression of Sox2, Sox11, Mash1, neurogenin1 or neurogenin2, although the level of expression of Sox11 and Mash1 appeared a little different from the wild-type, implying that Sox4 might indeed have a functional role in CNS development. However, since Sox4 and Sox11 expression is so similar, we propose that Sox11 might compensate for the loss of Sox4 function in the CNS such that the phenotype is extremely mild in the Sox4 null mutant.

Aging↗
PubMed2000

Localized brain activation by selective tasks improves specific cognitive functions in humans.

Neuroimaging studies have identified cognitive tasks that can selectively activate specific parts of the brains. However, the subsequent effect of localized brain activation on the cognitive functioning remains unclear. We discovered that after being engaged in the novel picture encoding task to activate hippocampus for 2 min, individuals demonstrated better memory, but not motor function. Similarly, after performing the finger sequencing task to activate the primary motor cortex, individuals showed improvement in motor function, but not in memory. These double dissociation results suggest that when we selectively activate specific part of the brain, the cognitive function mediated by that particular region but not the others can consequently be improved.

Adult↗
PubMed2000

Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis.

BACKGROUND: Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and temporal lobe necrosis is observed in about 7% of patients after radiotherapy. Although some studies reported that these patients demonstrated cognitive impairment after radiotherapy, it is still unclear if the cognitive deficits are related to the radiation exposure or the radiation-induced necrosis. OBJECTIVE: To compare the cognitive function of patients with and without temporal lobe necrosis after radiotherapy for nasopharyngeal carcinoma. METHODS: A comprehensive neuropsychological battery was administered to 53 patients with nasopharyngeal carcinoma who had completed their radiotherapy at least 1 year previously. As evidenced by magnetic resonance imaging, 31 patients developed necrosis after treatment. Thirty-one age- and education-matched individuals were recruited as normal control subjects. RESULTS: Whereas the performance of patients without temporal lobe necrosis was similar to that of normal control subjects, patients with temporal lobe necrosis demonstrated significant impairment on tests of verbal (P<.001) and visual memory (range, P<.001 to P =.03), language (range, P<.001 to P =.01), motor ability (P =.02), planning (P =.02), cognitive ability (P =.007), and abstract thinking (range, P =.009 to P =.04). However, the performance of patients with necrosis on tests of general intelligence (range, P =.08 to P =.15), attention (range, P =.06 to P =.55), and visual abilities (range, P =.06 to P =.47) was not significantly different from that of normal control subjects and patients without necrosis. CONCLUSIONS: Radiotherapy for nasopharyngeal carcinoma seemed to have adverse but insignificant effects on the cognitive functions of the patients. However, for patients who developed temporal lobe necrosis after radiotherapy, memory, language, motor ability, and executive functions were significantly impaired, although their general intelligence remained relatively intact.

Cognition Disorders↗
PubMed2000

Emotional responses to child sexual abuse: a comparison between police and social workers in Hong Kong.

OBJECTIVE: Research on specific emotional responses of professionals to child sexual abuse (CSA), other than the overwhelming feeling, is currently lacking in the child welfare literature. This study examines the initial responses to CSA of police and social workers in Hong Kong. METHOD: Based on their recall of the first child sexual abuse incident, 28 police officers and 86 social workers from 10 training sessions on child sexual abuse in Hong Kong indicated how strong they felt about their emotions in 10 categories of 37 responses. RESULTS: Among the 37 emotional responses, police and social workers showed significant differences in only seven responses: (1) embarrassment with the perpetrator; (2) ambivalence about rescuing the child or preserving the family; (3) fear of being inadequate in handling the situation; (4) titillation in response to our involuntary physiological responses to words and descriptions of sex acts; (5) feelings of revenge because the behavior was bad or immoral; (6) empathy with the child's condition; and (7) ambivalence about helping or punishing the perpetrator. In both groups, "anger at the perpetrator" and "empathy with the child's condition" were the most strongly felt emotions. CONCLUSIONS: Although these two professional groups were not significantly different in most of the emotional responses to their first child sexual abuse incidents, police were more likely to have ambivalent and revenge feelings, while social workers were more likely to have discomfort feelings. Limitations of this research project include sampling procedure, self-report biases, and effect of training.

Adult↗
PubMed2000

The unusual mammographic appearance of breasts augmented by autologous fat injection.

We report the case of a woman presenting to our centre with two breast lumps, 12 months after undergoing breast augmentation with autologous fat injection. Mammography showed a very unusual appearance, with most of the breast parenchyma displaced anteriorly by a large amount of fatty tissue. This was associated with extensive bizarre microcalcification, highlighting the difficulty in mammographic evaluation of this rare type of breast augmentation.

Journal Article↗
PubMed1999

Retroviral vector-mediated expression of hirudin by human vascular endothelial cells: implications for the design of retroviral vectors expressing biologically active proteins.

We constructed a hirudin cDNA cassette, HV-1.1, that encodes mature hirudin variant-1 fused to the signal peptide of human tissue-type plasminogen activator (t-PA). The cassette was subcloned into retroviral vectors and used to transduce human vascular endothelial cells in vitro. Hirudin antigen and activity were measured by ELISA and thrombin inhibition assays, respectively. Transduced cells secreted up to 35 +/- 2 ng/10(6) cells/24 h of biologically active hirudin; expression was stable for at least 7 weeks. Recombinant hirudin, expressed from the HV-1.1 cassette, had a specific activity of 7.1 +/- 0.2 antithrombin units per microgram (ATU/microgram), compared with specific activities of approximately 12 ATU/microgram for both native leech hirudin and recombinant hirudin produced in yeast. Protein sequencing and mass spectroscopic analysis revealed the presence of an extra N-terminal serine residue, indicating aberrant cleavage of the t-PA signal peptide and likely accounting for the diminished activity. We therefore constructed a second cDNA cassette, HV-1.2, in which hirudin secretion was directed by the signal peptide of human growth hormone. Hirudin expressed from the HV-1.2 cassette had a specific activity of 13.5 +/- 0.2 ATU/microgram. Protein sequencing and mass spectroscopic analysis demonstrated proper cleavage of the growth hormone signal peptide. Thus, we achieved high level retrovirus-mediated secretion of biologically active hirudin from endothelial cells in vitro. Use of these vectors may permit sustained local antagonism of thrombin activity in vivo.

Antithrombins↗
PubMed1998

Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDL-Atherosclerosis Treatment Study Design.

Evidence supports the idea that substantial benefits may derive from treatments that increase high density lipoprotein (HDL) cholesterol (HDL-C), apolipoprotein (apo) A-I, HDL2 (or 2b) or the size of HDL particles with, or without, apo A-II. HDL3 appears to be neutral in terms of coronary artery disease risk, and apo A-II appears to be adverse. Because HDL particles serve as antioxidants in vitro, the hypothesis that low HDL-C reflects an antioxidant deficiency state appears tenable. Based on these observations, a three-year angiographic study was proposed and received funding. Enrollment began in January 1995 and was completed in January 1997.

Adult↗
PubMed1997

Molecular cloning and chromatin structure analysis of the murine alpha1(I) collagen gene domain.

We have isolated molecular clones of genomic mouse DNA spanning 55 kb, including the entire coding region of the murine alpha1(I) collagen (Col1a1) gene and 24 kb of 5' and 13 kb of 3'-flanking sequences, and have performed a detailed chromatin structure analysis of these sequences. Several new DNase-I-hypersensitive sites were identified. The distal 5'-flanking region contains two clusters of DNase-I-hypersensitive sites located between 7 and 8 kb and between 15 and 20 kb upstream of the start site of transcription, respectively. Several of these sites were shown to be present in collagen-producing, but not in non-producing cells, indicating that they are associated with transcription of the gene and may function in its regulation. One strong constitutive DNase-I-hypersensitive site at -18.5 kb was also cleaved by endogenous nucleases. The 3'-flanking region of the gene contains a DNase-I-hypersensitive site located 6 kb downstream of the end of the gene, as well as sequences that can induce a non-B DNA structure. Because these latter sequences coincide with DNase-I-hypersensitive sites in the homologous human gene, our results suggest that some regulatory elements may play a role in gene regulation, not by specific protein-DNA interactions but by virtue of their ability to induce a non-B DNA structure and/or an alternate chromatin conformation. A comparison of the murine and human Col1a1 domains shows a similar, although not identical, distribution of DNase-I-hypersensitive sites, indicating a conserved arrangement of regulatory elements. Our results strongly suggest that these new sites constitute regulatory elements which are involved in the transcriptional regulation and/or chromatin loop organization of the Col1a1 gene, and they are now amenable for functional analyses.

3T3 Cells↗