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Biomedical subjects

W Cheung

Publications and source records attributed to W Cheung.

At least 19 recordsLinked to original sources
PubMed2006

Leptin and inflammation-associated cachexia in chronic kidney disease.

Leptin is an adipocyte-derived hormone that acts as a major regulator of food intake and energy homeostasis. It circulates both as a free and as a protein-bound entity. Leptin is released into the blood in proportion to the amount of body fat and exerts sustained inhibitory effects on food intake while increasing energy expenditure. The leptin receptor belongs to the class I cytokine receptor superfamily and possesses strong homology to the signal-transducing subunits of the IL-6 receptor. The hypothalamic melanocortin system, and specifically the melanocortin-4 receptor (MC-4R), is critical in mediating leptin's effect on appetite and metabolism. Serum leptin concentrations are elevated in patients with chronic kidney disease (CKD) and correlate with C-reactive protein levels suggesting that inflammation is an important factor that contributes to hyperleptinemia in CKD. Hyperleptinemia may be important in the pathogenesis of inflammation-associated cachexia in CKD. We showed that experimental uremic cachexia was attenuated in db/db mice, a model of leptin receptor deficiency. Nephrectomy in these animals did not result in any change in weight gain, body composition, resting metabolic rate, and efficiency of food consumption. Furthermore, experimental uremic cachexia could be ameliorated by blocking leptin signaling through the hypothalamic MC-4R. MC-4R knockout mice or mice administered the MC-4R and MC-3R antagonist, agouti-related peptide, resisted uremia-induced loss of lean body mass and maintained normal basal metabolic rates. Thus, melanocortin receptor antagonism may provide a novel therapeutic strategy for inflammation-associated cachexia in CKD.

Animals↗
PubMed2005

Outcomes of the morbidly obese having cardiac surgery.

OBJECTIVE: Obesity has been perceived to be a risk factor for adverse outcomes following cardiac surgery. The aim of this study was to test the hypothesis that patients with morbid obesity (defined as a body mass index (BMI) greater or equal to 40 kg/m(2)) would have increased rates of mortality and morbidity following cardiac surgery. METHODS: The case records of patients who had cardiac surgery between January 1996 and August 2002, who had a BMI greater or equal to 40 kg/m(2), were reviewed retrospectively and compared with a representative control group randomly selected from the same database. Differences between the two groups were determined using multiple and logistical regression. RESULTS: Out of the 4381 patients who had cardiac surgery, 28 patients were morbidly obese (0.6%). No morbidly obese patients and one control patient died in hospital (p = 0.31). Patients with morbid obesity had non-statistically significant increases in length of postoperative intensive care stay, hospital stay, infections, inotrope use and requirements for pacing. CONCLUSIONS: This study was unable to demonstrate that morbidly obese patients having cardiac surgery had statistically significant increased morbidity or mortality.

Journal Article↗
PubMed2004

Metabolism of the antineoplastic and immunosuppressive drug 2-CdA (Leustatin) in animals and humans.

1. The in vivo metabolism of the antineoplastic and immunosuppressive drug 2-CdA (Leustatin) was investigated in mice, monkeys and humans after a single subcutaneous dose of cladribine 60 mg kg(-1) to eight male and eight female mice and 10 mg kg(-1) to one male and one female monkey, and an intravenous infusion dose of cladribine 22-45 mg(-1) per subject to 12 male patients. 2. Plasma (1 h), red blood cells (1 h) and faecal samples (0-24 h) were obtained from mice and monkeys, and urine samples (0-24 h) were obtained from these species and humans. 3. Unchanged cladribine (urine: 47% of the sample in human; 60% of the sample in mouse; 73% of the sample in monkey) and 10 metabolites, consisting of four phase I metabolites (M1-3, M7) and six phase II metabolites -- five glucuronides (M4, M6, M8-10) and one sulfate (M5) -- were profiled, characterized and tentatively identified in plasma, red blood cells, and faecal and urine samples on the basis of API ionspray-mass spectrometry (MS) and MS/MS data. 4. Metabolites were formed via the following three metabolic pathways: oxidative cleavage at the adenosine and deoxyribose linkage (A); oxidation at adenosine/deoxyribose (B); and conjugation (C). 5. Pathways A and B appear to be major steps, forming four oxidative/cleavage metabolites (M1-3, M7) (each 3-20% of the sample). 6. Pathway C along or in conjunction with pathways A and B produced cladribine glucuronide, cladribine sulfate and four glucuronides of oxidative/cleavage metabolites in minor/trace quantities (each < or = 5% of the sample). 7. In addition, the in vitro metabolism of cladribine was conducted using rat and human liver microsomal fractions in the presence of an beta-nicotinamide adenine dinucleotide phosphate-generating system. Unchanged cladribine (> or = 90% of the sample) plus three minor metabolites, M1-3 (each < 8% of the sample), were profiled and tentatively identified by thin-layer chromatography and MS data. 8. Cladribine is not extensively metabolized in vitro and in vivo in all species. However, humans appear to metabolize cladribine to a greater extent than other animals.

Animals↗
PubMed2003

Childhood nephrotic syndrome in relapse is associated with down-regulation of monocyte CD14 expression and lipopolysaccharide-induced tumour necrosis factor-alpha production.

Interleukin-13 (IL-13) is a known modulator of monocyte function, down-regulating monocyte surface markers such as CD14 and proinflammatory cytokines. We have shown previously that lymphocyte IL-13 gene expression was up-regulated during relapses in children with steroid-responsive nephrotic syndrome (SRNS). In this study, we examined the monocyte mRNA expression and lipopolysaccharide (LPS)-stimulated intracellular production of tumour necrosis factor-alpha (TNF-alpha) and IL-8 in children with SRNS during relapse and remission. Additionally, we investigated CD14 mRNA levels, CD14 surface expression and its soluble component (sCD14) in serum. Our results showed that the percentages of TNF-alpha positive monocytes following LPS stimulation were significantly lower in nephrotic children in relapse (64.4 +/- 13.7%) compared to remission (81.6 +/- 9.0%, P < 0.005). This was associated with down-regulation of CD14 mRNA, as well as both membrane and sCD14 in patients with nephrotic relapse (82.9 +/- 10.1% and 1.23 +/- 0.30 micro g/ml, respectively) compared to remission (93.9 +/- 3.2% and 1.77 +/- 0.82 micro g/ml, respectively) (P < 0.003). Although we demonstrated a decrease in LPS-stimulated intracellular production of TNF-alpha in monocytes from patients with nephrotic relapse, we were unable to show a concomitant decrease in mRNA expression during relapses. This could be explained by down-regulation of gene expression at the translational rather than transcriptional level. In conclusion, it is conceivable that up-regulation of T-cell IL-13 production in children with active nephrotic relapse was associated with suppression of monocyte CD14 expression, down-regulating pro-inflammatory cytokine production, and could account for the increased susceptibility to bacterial sepsis seen in nephrotic children in active relapse.

Adolescent↗
PubMed2003

Lower neonatal screening thyroxine concentrations in down syndrome newborns.

There is an unexplained higher incidence of congenital hypothyroidism (CH) detected by T(4)-based neonatal screening programs and a very high prevalence of (mild) plasma TSH elevation in young children with Down syndrome (DS). To determine whether newborns with DS have decreased blood T(4) concentrations at the time of the neonatal screening, we conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. CH screening results (T(4), TSH, and T(4)-binding globulin concentrations) were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T(4) concentration of the studied children with DS (n = 284) was significantly decreased. The individual T(4) concentrations were normally (Gaussian) distributed but shifted to lower concentrations. This could not be explained by prematurity, nonthyroidal illness, or iodine exposure. Mean TSH and T(4)-binding globulin concentrations were significantly increased and normal, respectively. The decreased T(4) concentration, left-shifted normal distribution, and mildly elevated TSH concentrations point to a mild hypothyroid state in newborns with DS and support the existence of a DS-specific thyroid (regulation) disorder. The question remains whether this contributes to the brain maldevelopment.

Cohort Studies↗
PubMed2002

ACE gene polymorphism and disease progression of IgA nephropathy in Asians in Singapore.

The deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been considered as a risk factor for IgA nephropathy and for its progression to end-stage renal failure. However, results from various studies are conflicting. We had genotyped the ACE gene in 100 patients with IgA nephropathy, 32 of whom were in end-stage renal failure and in 90 normal adult subjects. All DD cases were subjected to confirmation with a second PCR, performed with the insert-specific forward primer. Similar genotype frequencies were obtained for the 90 normal control subjects (II: 47%, ID: 44%, DD: 9%); for the 68 patients not in end-stage renal failure (ESRF) (II: 47%, ID: 46%, DD: 7%) and for the 32 patients with ESRF (II: 53%, ID: 38%, DD: 9%). The genotype frequencies in all 3 series are in Hardy-Weinberg equilibrium. These results suggest that ACE gene polymorphism is not a risk factor for IgA nephropathy and is not a predictor for its progression. Definitive proof of association between ACE gene polymorphism and progression in IgA nephropathy will require a prospective study, controlled for important risk factors, with adequate patient numbers and facility for confirming DD genotypes.

Adult↗
PubMed2001

Pharmacokinetics and pharmacodynamics of epoetin alfa once weekly and three times weekly.

OBJECTIVE: To compare the pharmacokinetics, pharmacodynamics, and tolerance of epoetin alfa administered subcutaneously (s.c.) once weekly (q.w.) and three times weekly (t.i.w.). METHODS: An open-label, randomized, parallel-design study was conducted in 36 healthy adults with hemoglobin (Hb) levels of 11.7 14.0 g/dl for women and 13.0-14.8 g/dl for men. Subjects were randomized to epoetin alfa 150 IU/kg s.c. t.i.w. or 40,000 IU s.c. q.w. for 4 weeks. Serum erythropoietin concentrations were measured using a validated enzyme-linked immunosorbent assay (ELISA). Pharmacokinetic parameters [peak serum concentration (Cmax), mean predose trough concentration (Cmin), time to Cmax (tmax), clearance after s.c. administration (CL/F), area under the plasma concentration time curve (AUC), and terminal elimination half-life (t 1/2)] were calculated using model-independent methods. Mean changes from baseline and AUC of percentage reticulocytes, Hb, and total red blood cell (RBC) concentrations over the 1-month study period were calculated. RESULTS: The Cmax values for serum epoetin alfa q.w. were six times and AUC(0-168) values three times that of the t.i.w. regimen. Time profiles of changes in percentage reticulocytes, Hb, and total RBC over 1 month were similar between regimens. The rate of increase in Hb was similar for the two groups, and both groups exhibited a 3.1-g/dl increase in mean Hb levels from baseline through day 29. Changes in ferritin levels were generally similar between groups and reflected expected use of iron stores for Hb production. Epoetin alfa administered t.i.w. or q.w. was well tolerated and no serious adverse events occurred. CONCLUSION: The pharmacodynamic responses were equivalent between groups despite expected differences in total erythropoietin exposure. These results indicate that the epoetin alfa 150 IU/kg t.i.w. and 40,000 IU q.w. regimens can be considered clinically equivalent.

Adolescent↗
PubMed2000

Identification of RS as a flagellar and head sperm protein.

RS is 20-kDa microtubule-associated protein found in several human tissues. Sequence analysis showed that the polypeptide is highly related to a rat protein whose level has been previously reported to be correlated with sperm fertility. The present study examines the intracellular distribution of RS in spermatozoa from both humans and rats employing a specific antibody to the polypeptide and immunofluorescence microscopy. We demonstrate that in humans, RS is mainly a flagellum protein, but in rats, it is also abundant in the sperm head. In the sperm tail, RS was found to be co-localized with beta-tubulin, a major component of the axoneme, suggesting that RS is also associated with the flagellum axoneme. Contrary to a previous report, incubation of isolated spermatozoa from both humans and rats in the presence of ornidazole, a reported male contraceptive drug in rats, did not result in modulation in the level of RS, suggesting that the drug does not act directly on sperm RS. Mol. Reprod. Dev. 55:189-196, 2000.

Amino Acid Sequence↗
PubMed2000

Minimal change nephrotic syndrome--a complex genetic disorder.

INTRODUCTION: Minimal change nephrotic syndrome (MCNS) is the most common primary nephrotic syndrome in childhood. While the pathogenesis of this disease is still unknown, there is considerable evidence that it is an immune disease. This role of genetic susceptibility in this disease is the subject of this review. METHODS: Reported studies addressing potential genetic factors in MCNS were reviewed. These factors included human leukocyte antigen (HLA) associations, genes involved in the renin-angiotensin system and cytokines. RESULTS: Several authors have reported the presence of familial clustering, human leukocyte antigen (HLA) associations, and association with asthma and atopy, suggesting a genetic susceptibility to the disease. Moreover, recent studies on the role of the renin angiotensin system, cytokines and their respective receptors on the severity and clinical course of the disease, have lent further support to the immunogenetic basis of this disease. CONCLUSION: Knowledge of the genetic basis of MCNS may have important therapeutic implications in this disease, in particular, the role of cytokines and their respective receptors, including the influence of environmental factors on their expression.

Cytokines↗
PubMed1999

Balance and physical impairments after stroke.

OBJECTIVE: To investigate the relationship among laboratory and clinical balance measures and physical impairments. DESIGN: A descriptive correlational study. SETTING: Research laboratory. PARTICIPANTS: Thirty subjects with stroke, recruited through convenience sampling. MAIN OUTCOME MEASURES: Postural sway was calculated in terms of center of pressure (COP) parameters including spectral characteristics. Clinical balance was measured using the Balance Scale. The assessed physical impairments included stages of lower limb motor recovery, ankle proprioception, and passive dorsiflexion range of the involved limb. RESULTS: The Balance Scale was correlated with COP speed (r = -.57), COP root mean square speed (r = -.50), and COP mean frequency (r = -.50) in the anterior-posterior direction only. Moderate to high correlations were found among most of the COP parameters except spectral characteristics. Significant differences in postural sway were found among different stance in eyes-open (p = .00 to .02) and eyes-closed conditions (p = .00 to .04). Subjects with impaired ankle proprioception had significantly increased postural sway and decreased Balance Scale scores when compared with the subjects with intact ankle proprioception. CONCLUSIONS: Some of the clinical and laboratory balance assessments were related, indicating that some components of the tests are similar, but some measured different aspects of balance. Postural sway was related to visual condition, stance position, and proprioception.

Activities of Daily Living↗
PubMed1999

Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse.

Idiopathic nephrotic syndrome of childhood is thought to be associated with T lymphocyte dysfunction often triggered by viral infections, with the production of circulating factor(s) resulting in proteinuria. In view of the conflicting evidence of T cell activation and Th1 or Th2 pattern of cytokine synthesis in this disease, this study examined the mRNA expression of interleukin-2 (IL-2), interferon-gamma, IL-4, and IL-13 from CD4+ and CD8+ T cells in steroid-responsive nephrotic patients in relapse and remission. Fifty-five children with steroid-responsive nephrotic syndrome were included in this study, together with 34 normal controls and 24 patient controls with viral infections. RNA was isolated from purified CD4+ or CD8+ cells from peripheral blood and subjected to reverse transcription-PCR. Cytokine mRNA expression was measured semiquantitatively, and a cytokine index was derived from densitometric readings, with cyclophilin as the housekeeping gene. Both cross-sectional and paired data showed an increased CD4+ and CD8+ IL-13 mRNA expression in patients with nephrotic relapse as compared to remission, normal, and patient controls (P < 0.008). This was also associated with increased cytoplasmic IL-13 expression in phorbol myristate acetate/ionomycin-activated CD3+ cells (6.66+/-3.39%) from patients with nephrotic relapse compared to remission (2.59+/-1.35%) (P < 0.0001). However, there was no significant difference in CD4+ or CD8+ IL-2, interferon-gamma and IL-4 mRNA expression. IL-13 is an important T cell cytokine with anti-inflammatory and immunomodulatory functions on B cells and monocytes. It is conceivable that IL-13 may act on monocytes to produce vascular permeability factor(s) involved in the pathogenesis of proteinuria in patients with relapse nephrotic syndrome.

Adolescent↗
PubMed1998

Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A.

The NMDA (N-methyl-D-aspartate) subclass of glutamate receptor is essential for the synaptic plasticity thought to underlie learning and memory and for synaptic refinement during development. It is currently believed that the NMDA receptor (NMDAR) is a heteromultimeric channel comprising the ubiquitous NR1 subunit and at least one regionally localized NR2 subunit. Here we report the characterization of a regulatory NMDAR subunit, NR3A (formerly termed NMDAR-L or chi-1), which is expressed primarily during brain development. NR3A co-immunoprecipitates with receptor subunits NR1 and NR2 in cerebrocortical extracts. In single-channel recordings from Xenopus oocytes, addition of NR3A to NR1 and NR2 leads to the appearance of a smaller unitary conductance. Genetic knockout of NR3A in mice results in enhanced NMDA responses and increased dendritic spines in early postnatal cerebrocortical neurons. These data suggest that NR3A is involved in the development of synaptic elements by modulating NMDAR activity.

Animals↗
PubMed1998

Paternal height and weight as determinants of birth weight in a Chinese population.

To evaluate the relationship between paternal weight and height and birth weight, 355 middle class patients with uncomplicated singleton pregnancies who booked within the first trimester were recruited from a homogenous obstetric population from a teaching hospital unit. Maternal height and prepregnant maternal weight were recorded at the booking visit. Paternal height and weight were recorded when the fathers entered the labor ward or visited the postnatal ward at or shortly after the time of delivery. These data were then correlated with the birth weight of the babies. There was a significant correlation between paternal height and weight and the corresponding maternal parameters (correlation coefficients 0.21, p<0.001 and 0.21, p < 0 > 0.01). When the crude birth weight was adjusted for the gestation at delivery, and then controlled for maternal height and weight with the use of a regression model, analysis of variance tests showed that paternal height was significantly correlated to the adjusted birth weight (p<0.01), while paternal weight only showed a marginal correlation (p = 0.05). There was a significant correlation between maternal and paternal height and weight, indicating that couples tend to be of similar sizes. When controlling for maternal size, paternal height was significantly correlated to birth weight, while paternal weight showed only marginal significance. The data suggested that paternal genetic influence could be a significant determinant of in utero fetal growth and thus birth weight.

Adult↗
PubMed1998

The relationship between weight gain in pregnancy, birth-weight and postpartum weight retention.

A total of 292 middle class, nonsmoking Chinese patients with known prepregnant weight who subsequently had uncomplicated singleton pregnancies delivering after 36 weeks' gestation were recruited to assess their serial antenatal weight gain, weight at 6 weeks and 3 months postpartum. The average prepregnant body mass index in the whole group was 20.4 kg/m2 (SD 2.19), and the total pregnancy weight gain was 14 kg (SD 3.75). Those with weight gain over 17.83 kg (one SD above the mean) (n=58) had higher weight gain in all 3 trimesters taken separately, as well as higher weight retention at 6 weeks and 3 months postpartum (p <0.001). Similar differences were noted for those with total weight gain over 2 standard deviations above the mean. The average weight retained at 3 months postpartum was 3.64 kg (SD 2.75). Those with weight retention over 9.14 kg (2 SD above the mean) (n=8) had a significantly higher second and third trimester weight gain (p <0.01) compared to the rest. These data suggest that excessive weight gain during pregnancy for women with prepregnant BMI in the normal range occurred most significantly after the mid-trimester, and was associated with higher postpartum weight retention without significant increase in birth-weight.

Birth Weight↗