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Biomedical subjects

Wai Cheung

Publications and source records attributed to Wai Cheung.

17 recordsLinked to original sources
PubMed2007

Cachexia in chronic kidney disease: role of inflammation and neuropeptide signaling.

PURPOSE OF REVIEW: This review will update clinicians and basic scientists who are interested in the clinical relevance and molecular mechanism of uremic cachexia. Recent studies that examine the role of cytokines and hypothalamic neuropeptides are emphasized. RECENT FINDINGS: A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate. Proinflammatory cytokines also activate the transcription factor nuclear factor-kappaB, resulting in decreased protein synthesis, and activate the ubiquitin-mediated proteolytic system, which is the major system involved in increased protein degradation. SUMMARY: This review highlights the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and the potential of peripheral administration of melanocortin-4 receptor antagonists as a novel therapeutic approach.

Anorexia↗
PubMed2006

Energy homeostasis and cachexia in chronic kidney disease.

Loss of protein stores, presenting as clinical wasting, is reported to have a prevalence of 30-60% and is an important risk factor for mortality in chronic kidney disease (CKD) patients. There is debate as to whether the clinical wasting in CKD patients represents malnutrition or cachexia. Malnutrition results from inadequate intake of nutrients, despite a good appetite, and manifests as weight loss associated with adaptive metabolic responses such as decreased basic metabolic rate and preservation of lean body mass at the expense of fat mass. Furthermore, the abnormalities in malnutrition can usually be overcome simply by supplying more food or altering the composition of the diet. In contrast, cachexia is characterized by maladaptive responses such as anorexia, elevated basic metabolic rate, wasting of lean body tissue, and underutilization of fat tissue for energy. Diet supplementation and intradialytic parenteral nutrition have not been successful in reversing cachexia in CKD. The etiology of cachexia in CKD is complex and multifactorial. Two major factors causing muscle wasting in uremia are acidosis and decreased insulin responses. Inflammation secondary to cytokines may also play a significant role. The hypoalbuminemia of CKD patients is principally associated with inflammation and not changes in food intake. There is also recent evidence that hypothalamic neuropeptides may be important in the downstream signaling of cytokines in the pathogenesis of cachexia in CKD. Elevated circulating levels of cytokines, such as leptin, may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system. Further research into the molecular pathways leading to cachexia may lead to novel therapeutic therapy for this devastating and potentially fatal complication of CKD.

Animals↗
PubMed2006

Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia.

Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30-60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome--more accurately described as 'cachexia'--manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-alpha, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia.

Adipose Tissue↗
PubMed2006

CD14 promoter polymorphisms have no functional significance and are not associated with atopic phenotypes.

OBJECTIVES: A polymorphism at CD14/-159 has been reported to be associated with atopic phenotypes in several studies. However, conflicting results from association studies in different populations have been reported. This study aimed to investigate the relationship between CD14 promoter polymorphisms and atopic phenotypes in Singaporean Chinese and the biological characterization of these polymorphisms. METHODS: A total of 171 atopic and 160 non-atopic adult subjects were included and their serum soluble CD14 (sCD14) and total immunoglobulin E (tIgE) levels were measured. Screening of single nucleotide polymorphisms (SNPs) in the CD14 promoter was performed using direct PCR-sequencing and restriction fragment length polymorphism methods. The functional significance of SNPs was investigated using reporter assay system. RESULTS: Three previous reported SNPs (CD14/-159, -1145 and -1359) and a novel SNP (CD14/-550) were detected. Significant linkage disequilibrium was found among these four loci of CD14 gene. However, no significant difference was found in the genotype frequencies of these SNPs between non-atopy and atopy groups. Furthermore, no transcriptional activities of these SNPs were detected using reporter gene assay in three cell-lines (HepG-2, THP-1 and U937). CONCLUSIONS: This study confirms three reported SNPs and one novel SNP in the CD14 promoter in our local population. However, these SNPs do not play a decisive role in the development of atopic phenotypes.

Adult↗
PubMed2005

Reduced transcriptional activity in individuals with IL-18 gene variants detected from functional but not association study.

Genetic polymorphisms of IL-18 and its receptor were reported to be associated with elevated serum IgE levels, atopy, and/or asthma. However, conflicting results were observed in various association studies and functional activity of these polymorphisms remains unclear. A total of 393 unrelated subjects were involved in this study. Direct PCR-sequencing method was used to screen novel polymorphisms. The functional significance of these polymorphisms was investigated using reporter gene assay. Three known (-137, +113, and +127) polymorphisms in the IL-18 promoter were identified with a perfect linkage disequilibrium (Delta=1, p<0.001) among them. No significant difference in the genotype frequencies of these polymorphisms between atopy and atopic phenotypes in Singaporean Chinese, Malays, and Indians was observed. However, transcriptional activities were significantly increased in HepG2 cultured cells with wild-type IL-18 genotype (-137/G, +113/T, and +127/C) than mutated genotype (-137/C, +113/G, and +127/T). Although these polymorphisms appear to have no association with atopic phenotypes in our population, subsequent functional studies suggest that polymorphisms in the IL-18 promoter region could affect significantly its activity.

Adult↗
PubMed2005

Interleukin-13 genetic polymorphisms in Singapore Chinese children correlate with long-term outcome of minimal-change disease.

BACKGROUND: Minimal-change nephrotic syndrome (MCNS) has been associated with atopy. As interleukin-13 (IL-13) has been implicated in the pathogenesis of MCNS, we postulated that IL-13 genetic polymorphisms could influence either susceptibility or clinical course of the disease. METHODS: Seventy-two Singapore Chinese children with MCNS and 78 normal controls were screened for single nucleotide polymorphisms (SNPs) in the IL-13 gene by direct sequencing. Allele and genotype frequencies of these SNPs were determined and their relationship with different clinical courses was analysed. RESULTS: Six SNPs were identified in the 5' promoter, exon 4 and 3' untranslated region (3'UTR). The three SNPs in the 3'UTR--4738 (G/A), 4793 (C/A) and 4926 (C/T)--were in tight linkage disequilibrium (Delta > or = 0.99). There was no difference in allele or genotype frequencies between MCNS children and normal controls. However, there was a significantly lower frequency of allele 4738G in those MCNS children who were still relapsing after 5 years of follow-up (G = 0.52), compared with those in complete remission (G = 0.72; P<0.05) and normal controls (G = 0.69; P<0.05). Haplotype analysis showed a significantly higher frequency of the GCC haplotype in controls and MCNS patients in complete remission (chi2 = 6.35; P<0.02), while the frequency of AAT haplotype was higher in those MCNS children still relapsing after 5 years of follow-up (chi2 = 5.38; P<0.02). Moreover, peripheral blood mononuclear cell IL-13 mRNA expression in patients with haplotype AAT was significantly higher than in those with haplotype GCC. CONCLUSIONS: These results suggest that genetic polymorphisms in the 3'UTR of the IL-13 gene correlate with long-term outcome of MCNS, rather than disease susceptibility, in Singapore Chinese children.

Child↗
PubMed2005

Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease.

Malnutrition is defined as abnormalities caused by an inadequate diet, but this term is often used inappropriately to describe the syndrome of loss of body weight with muscle mass being replaced by fatty tissue and declining serum proteins present in adults and children with chronic kidney disease (CKD). This syndrome is more accurately described as cachexia, and manifests as growth failure in children with CKD. Cachexia is common and is an important risk factor for poor quality of life and increased mortality and morbidity in both adults and children with CKD. Anorexia, acidosis and inflammation are important causes of cachexia, but the underlying molecular mechanism is not well understood. Dietary intake is often poor and resting metabolic rate is increased in CKD. The energy cost of growth is increased in experimental CKD. Circulating concentrations of cytokines, such as leptin, tumor necrosis factor-alpha and interleukins 1 and 6 are increased in patients with CKD and correlate with the degree of cachexia in these individuals. We hypothesize that cytokines signal through orexigenic neuropetides such as agouti-related peptide and neuropeptide Y (NPY), and anorexigenic neuropetides such as proopiomelanocortin and alpha-melanocyte-stimulating hormone in the arcuate nucleus in the hypothalamus. This signaling system also involves the NPY receptor and the melanocortin receptors and controls appetite and metabolic rate in health and disease. Furthermore, the first order neurons of this system are located outside the blood-brain barrier and can therefore sense the circulating levels of cytokines, as well as long-term satiety hormones such as leptin and insulin and short-term satiety hormones such as ghrelin and peptide (P) YY. There is experimental evidence that this hypothalamic neuropeptide signaling system may have an important role in the pathogenesis of cachexia in CKD. Understanding the molecular mechanism of cachexia in CKD may lead to novel therapeutic strategies.

Cachexia↗
PubMed2005

Role of leptin and melanocortin signaling in uremia-associated cachexia.

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

Agouti-Related Protein↗
PubMed2004

Atopy, serum IgE, and interleukin-13 in steroid-responsive nephrotic syndrome.

Earlier studies have demonstrated a strong association of steroid-responsive nephrotic syndrome (SRNS), atopy, and elevated serum IgE levels. Interleukin (IL-13) gene expression is significantly increased in children with SRNS in relapse. As interferon (IFN)-gamma, IL-13, and IL-4 have regulatory effects on IgE synthesis, we examined the relationship between intracellular cytokine production and serum IgE levels in children with SRNS, in order to further define the reported association with atopy. The median serum IgE levels in nephrotic patients in relapse with (492 U/ml) or without atopy (561 U/ml) were significantly higher than those in remission (221 U/ml, P<0.002 or 90 U/ml, P<0.001, respectively) and non-atopic controls (177 U/ml) (P<0.001). The percentage of CD3+ IL-13-producing cells was significantly higher in nephrotic children in relapse, and correlated with the serum IgE levels during the active phase of the disease (r=0.90, P<0.001). These data suggest that the elevated serum IgE levels during relapses of SRNS were the result of upregulation of IL-13. This probably reflects some common immune activation following various stimuli, rather than a direct association with atopy.

Adolescent↗
PubMed2003

A randomised comparison of side effects and patient inconvenience of two vaginal progesterone formulations used for luteal support in in vitro fertilisation cycles.

OBJECTIVE: To compare side effects and patient inconvenience of two vaginal progesterone (P) formulations for luteal support in in vitro fertilisation cycles. STUDY DESIGN: Sixty infertile patients at risk of developing ovarian hyperstimulation syndrome were randomised to receive either Cyclogest vaginal suppositories 400mg twice daily or Crinone 8% vaginal gel once daily for 14 days as the luteal support. On Day 6 and Day 16 after embryo transfer, they rated side effects and patient inconvenience into four grades: none, mild, moderate and severe by completing a questionnaire. RESULTS: Perineal irritation was reported by about 20% of patients in each group. Significantly more patients using Cyclogest suppositories graded inconvenience of administration, leaking out and interference with coitus as moderate or severe. CONCLUSION: There was no difference in perineal irritation after Cyclogest suppositories or Crinone 8% gel although significantly more patients found inconvenience of administration, leaking out and interference with coitus after Cyclogest.

Administration, Intravaginal↗
PubMed2003

IL-10 synergistically enhances GM-CSF-induced CCR1 expression in myelomonocytic cells.

CC chemokine receptor 1 (CCR1) has been implicated in inflammation. The present study examined the signaling mechanisms that mediate GM-CSF/IL-10-induced synergistic CCR1 protein expression in monocytic U937 cells. GM-CSF alone markedly increased both the mRNA and protein expression of CCR1. IL-10 augmented GM-CSF-induced CCR1 protein expression with no effect on mRNA expression. PD098059 and U0126 (two MEK inhibitors), and LY294002 (a PI3K inhibitor) inhibited GM-CSF/IL-10-induced CCR1 gene and protein expression. PD098059, U0126, and LY294002 also attenuated chemotaxis of GM-CSF/IL-10-primed U937 cells in response to MIP-1alpha. Immunoblotting studies show that GM-CSF alone induced ERK2 phosphorylation; whereas, IL-10 alone induced p70(S6k) phosphorylation in U937 cells. Neither cytokine when used alone induced PKB/Akt phosphorylation. Combined GM-CSF/IL-10 treatment of U937 cells induced phosphorylation of ERK2, p70(S6k), and PKB/Akt. PD098059 and U0126 completely abrogated ERK2 phosphorylation; whereas, LY294002 completely blocked PKB/Akt and p70(S6k) phosphorylation. Our findings indicate that IL-10 may potentiate GM-CSF-induced CCR1 protein expression in U937 cells via activation of PKB/Akt and p70(S6k).

Chemokine CCL3↗
PubMed2003

Pilot study on the use of sublingual misoprostol in termination of pregnancy up to 7 weeks gestation.

BACKGROUND: This study was conducted to assess the efficacy and incidence of side effects of a regimen of repeated doses of 400 microg sublingual misoprostol for termination of pregnancy of <7 weeks gestation. METHOD: Fifty women were given 400 microg sublingual misoprostol every 3 h for three doses. Two additional doses were given if necessary. RESULTS: Forty-three women (86%) had a complete abortion. Two women (4%) had incomplete abortion and 5 (10%) had an ongoing pregnancy. The median interval between the first dose of misoprostol and the passage of tissue mass was 14.1 h (3.25-561.6 h). The median duration of vaginal bleeding was 20 days (8-85 days). Side effects were mild and there was no significant drop in hemoglobin level. CONCLUSIONS: Our preliminary results on sublingual misoprostol show that it is a promising method for medical termination of pregnancy of <7 weeks. It may be used as an alternative for women who do not want surgical evacuation and who live in an area where mifepristone is not available.

Abortifacient Agents, Nonsteroidal↗
PubMed2003

Hepatitis B surface antigen carrier status and its correlation to gestational hypertension.

OBJECTIVE: To determine whether chronic hepatitis B surface antigen (HBsAg) carrier status is associated with an increased incidence of gestational hypertension. METHODS: A retrospective analysis of all deliveries in a regional obstetric unit over a 4-year period using a comprehensive obstetric database. RESULTS: The data of 13,792 patients were analysed, of which 1340 (9.71%) were chronic HBsAg carriers. Contrary to our hypothesis, the overall incidence of gestational hypertension was significantly lower in the HBsAg positive group (2.01%) as compared to the negative group (3.58%) (P < 0.01, odds ratio (OR) 0.55, 95% confidence interval (CI) 0.37-0.81). When comparing the incidence of severe preeclampsia, the difference remained significant (0.22 and 0.79%, respectively, P < 0.05, OR 0.28, 95% CI 0.08-0.88). There was otherwise no difference in the incidence of other major obstetric complications between the HBsAg positive and negative groups. CONCLUSION: The findings presented did not support a positive association between HbsAg carrier status and gestational hypertension. The data from the present study, and re-evaluation of similar published data, in fact suggest the contrary observation of a lower than normal incidence of gestational hypertension in HbsAg positive mothers.

Adult↗
PubMed2002

Increased HLA- A*11 in Chinese children with steroid-responsive nephrotic syndrome.

Human leukocyte antigen (HLA) associations have been frequently reported in childhood steroid-responsive nephrotic syndrome (SRNS) in other populations. The aim of this study was to characterize the immunogenetic background of Singaporean Chinese patients with childhood SRNS. We determined the HLA class I (HLA- A* and HLA-B*) as well as class II (HLA- DRB1*, HLA- DQB1*) gene polymorphisms using the polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) technique, in patients with SRNS (n=64) and normal controls (n=236 for HLA- A*, n=80 for HLA- B*, HLA- DRB1* and HLA- DQB1*). The frequency of HLA- A*11 allele was significantly higher in the SRNS patients compared to controls (78.1% vs 54.2%, respectively; relative risk, RR=3.01, Pc=0.011). However, there was no significant difference in the allele frequencies of HLA- B*, HLA- DRB1* and HLA- DQB1* between the SRNS patients and controls, unlike that in previous studies. Our data suggest that the immunogenetic background of Singaporean Chinese with childhood SRNS was different from that in other populations. As HLA- A*11 has been strongly associated with other autoimmune diseases, it is conceivable that the HLA- A*11-specific motif may play a role in the development of the abnormal T-cell-mediated immune response that may be responsible for triggering the proteinuria seen in SRNS.

Adrenal Cortex Hormones↗
PubMed2002

A randomized double-blind comparison of perifollicular vascularity and endometrial receptivity in ovulatory women taking clomiphene citrate at two different times.

BACKGROUND: It is still controversial whether the day of clomiphene citrate initiation has any impact on the pregnancy rate. This study aimed to compare the perifollicular vascularity and endometrial receptivity of ovulatory women who started clomiphene citrate on day 2 and day 5. METHODS: Thirty-five women with regular ovulatory cycles were first monitored in a natural cycle and then randomized by computer-generated random numbers put in sealed opaque envelopes to receive 50 mg clomiphene citrate on days 2-6 or on days 5-9. The hormonal profile, the number of dominant follicles, the grading of perifollicular vascularity, endometrial thickness and Doppler flow indices of uterine/subendometrial arteries were compared between both groups. RESULTS: All the above parameters were similar for both groups on the day of the LH surge and 7 days after the LH surge. CONCLUSIONS: There were no differences in oocyte quality graded by the perifollicular vascularity and the endometrial receptivity assessed by endometrial thickness and Doppler flow indices of uterine and subendometrial vessels when clomiphene citrate was started in regularly ovulatory women on day 2 or on day 5.

Adult↗