Publications by authors named "Michael Ho Ming Chan"

29 Publications

  • Page 1 of 1

Prenatal methylmercury exposure is associated with decrease heart rate variability in children.

Environ Res 2021 09 23;200:111744. Epub 2021 Jul 23.

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong. Electronic address:

Background: Although several epidemiological studies have suggested mercury (Hg) might be associated with cardiotoxicity, the impact of Hg exposure on cardiac autonomic activity and blood pressure in children has not been investigated at Hg exposure levels equivalent to the Environmental Protection Agency (EPA) reference dose.

Objective: To investigate the association between low dose prenatal and recent methylmercury (MeHg) exposures and cardiac autonomic function and blood pressure with adjustment for factors such as fish consumption among children from a high fish consumption coastal city.

Methods: Children aged 7-8 years were recruited from the birth cohort of our previous study. Heart rate variability (HRV), resting heart rate (RHR) and blood pressure were measured as surrogate markers of cardiac autonomic function. Cord blood and current whole blood Hg concentration were used as biomarkers of prenatal and recent MeHg exposure, respectively. Recent fish consumption information was estimated with a food frequency questionnaire.

Results: Among 604 children, median cord blood and whole blood Hg concentrations were 45.9 nmol/L (IQR: 32.8-65.03 nmol/L) and 13.57 nmol/L (IQR: 9.29-19.72 nmol/L), respectively. Our results demonstrated that prenatal MeHg exposure was associated with decreased HRV (i.e. low CVRR, SDRR, and RMSSD), reflecting reduced parasympathetic activity (i.e. low CCV and HF), and a sympathovagal balance shift toward sympathetic predominance (i.e. high %LF and LF/HF ratio). Adjustment of recent fish consumption further increased the significance and magnitude of the adverse associations of MeHg.

Conclusion: The results of this study suggest that prenatal MeHg exposure is associated with decreased parasympathetic modulation of cardiac autonomic function in children.
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September 2021

Association between genetic variations in GSH-related and MT genes and low-dose methylmercury exposure in children and women of childbearing age: a pilot study.

Environ Res 2020 08 20;187:109703. Epub 2020 May 20.

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region. Electronic address:

Background: Genetic variations in glutathione (GSH)-related and metallothionein (MT) genes, which are involved in producing enzymes in the methylmercury (MeHg) metabolism pathway, have been proposed as one of the reasons for the individual variability in MeHg toxicokinetics.

Objective: To investigate the impact of genetic variations in MT and GSH-related genes on the association of fish consumption with body burden of MeHg, as measured by hair Hg concentrations among young children and women of childbearing age.

Methods: A total of 179 unrelated children and 165 mothers with either high or low fish consumption were recruited from the community. Their hair total Hg (tHg) and MeHg levels and genotypes for SNPs located on the GCLC, GCLM, GPX1, GSTA1, GSTP1, MT1A, MT2A, and MT4 genes were determined. Based on their 14-day food records, the amounts of fish consumed and their MeHg intakes were estimated. The impact of genetic variations on hair Hg concentrations was examined by using Mann-Whitney tests and multivariable linear regression analyses.

Results: The presence of minor alleles of GCLC-129 (rs17883901), GPX1-198 (rs1050450) and MT1M (rs9936741) were associated with significantly lower hair tHg levels in mothers whereas mothers with minor alleles of GSTP1-105(rs1695) and MT1M (rs2270836) have significantly higher hair tHg levels. After adjustment for fish consumption and other confounding factors, apart from MT1M (rs2270836), all of the above SNPs remain significant in the multivariable linear regression models.

Conclusions: Our results in a group of children and women show that genetic variants of GSH-related and MT genes are associated with hair Hg concentrations. These genetic variations are likely to significantly affect MeHg metabolism and thus influence the accumulation of Hg in the human body.
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August 2020

Development of Gestational Age-Specific Thyroid Function Test Reference Intervals in Four Analytic Platforms Through Multilevel Modeling.

Thyroid 2020 04 21;30(4):598-608. Epub 2020 Feb 21.

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, New Territories, Hong Kong.

A population-based reference interval (RI) of thyroid hormones in pregnancy using a standardized methodology is crucial for clinicians to make accurate diagnoses and important for the comparison of test results obtained from different analytic platforms. We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation, after exclusion of subjects with antibodies to thyroid peroxidase, thyroglobulin or thyrotropin receptor. Gestational age-specific RIs were constructed by using polynomial regression equations with MLwiN. Free thyroxine (fT4) levels rose to a peak at the 7th-8th gestational weeks and then declined gradually till 28th week, while thyrotropin (TSH) level decreased from early pregnancy to a nadir at the 9th week. The data support the recent notion by the American Thyroid Association to raise the TSH upper RI to 4.0 mIU/L. We also demonstrate that thyroid hormone reference ranges are not affected in a mildly iodine-deficient population and by including women with the presence of antibodies against thyroid peroxidase and thyroglobulin who are otherwise healthy. The study highlights a methodology in constructing gestational age-specific thyroid function test RIs on different analytic platforms to provide a better interpretation and comparison of results obtained across different platforms.
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April 2020

A Hong Kong Chinese kindred with familial hypocalciuric hypercalcaemia caused by mutation.

F1000Res 2019 9;8:1612. Epub 2019 Sep 9.

Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong.

Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder of altered calcium homeostasis. Mutations in the , and genes have been reported to cause FHH. We report a Hong Kong Chinese kindred with FHH type 3 (FHH3) caused by mutations in . The proband, a 51-year-old woman with hypercalcaemia, was initially diagnosed to have primary hyperparathyroidism but repeated parathyroidectomy failed to normalize her plasma calcium concentrations. Later, FHH was suspected and yet no mutations were identified in the gene which causes FHH type 1 (FHH1), the most common form of FHH. Genetic testing of revealed a heterozygous c.43C>T (p.Arg15Cys) mutation, confirming the diagnosis of FHH3. The elder brother and niece of the proband, who both have hypercalcaemia, were found to harbour the same mutation. To our knowledge, this is the first Chinese kindred of FHH3 reported in the English literature.
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June 2020

Progression of glucose intolerance and cardiometabolic risk factors over a decade in Chinese women with polycystic ovary syndrome: A case-control study.

PLoS Med 2019 10 25;16(10):e1002953. Epub 2019 Oct 25.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.

Background: Polycystic ovary syndrome (PCOS) is associated with increased metabolic risk, though data on long-term follow-up of cardiometabolic traits are limited. We postulated that Chinese women with PCOS would have higher risk of incident diabetes and cardiometabolic abnormalities than those without PCOS during long-term follow-up.

Methods And Findings: One hundred ninety-nine Chinese women with PCOS diagnosed by the Rotterdam criteria and with a mean age of 41.2 years (SD = 6.4) completed a follow-up evaluation after an average of 10.6 ± 1.3 years. Two hundred twenty-five women without PCOS (mean age: 54.1 ± 6.7 years) who underwent baseline and follow-up evaluation over the same period were used for comparison. Progression of glycaemic status of women both with and without PCOS was assessed by using 75-g oral glucose tolerance test (OGTT) screening with the adoption of 2009 American Diabetes Association diagnostic criteria. The frequency of impaired glucose regulation, hypertension, and hyperlipidaemia of women with PCOS at follow-up has increased from 31.7% (95% CI 25.2%-38.1%) to 47.2% (95% CI 40.3%-54.2%), 16.1% (95% CI 11.0%-21.2%) to 34.7% (95% CI 28.1%-41.3%), and 52.3% (95% CI 45.3%-59.2%) to 64.3% (95% CI 57.7%-71.0%), respectively. The cumulative incidence of diabetes mellitus (DM) in follow-up women with PCOS is 26.1% (95% CI 20.0%-32.2%), almost double that in the cohort of women without PCOS (p < 0.001). Age-standardised incidence of diabetes among women with PCOS was 22.12 per 1,000 person-years (95% CI 10.86-33.37) compared with the local female population incidence rate of 8.76 per 1,000 person-years (95% CI 8.72-8.80) and 10.09 per 1,000 person-years (95% CI 4.92-15.26, p < 0.001) for women without PCOS in our study. Incidence rate for women with PCOS aged 30-39 years was 20.56 per 1,000 person-years (95% CI 12.57-31.87), which is approximately 10-fold higher than that of the age-matched general female population in Hong Kong (1.88 per 1,000 person-years, [95% CI 1.85-1.92]). The incidence rate of type 2 DM (T2DM) of both normal-weight and overweight women with PCOS was around double that of corresponding control groups (normal weight: 8.96 [95% CI 3.92-17.72] versus 4.86 per 1,000 person-years [95% CI 2.13-9.62], p > 0.05; overweight/obese: 28.64 [95% CI 19.55-40.60] versus 14.1 per 1,000 person-years [95% CI 8.20-22.76], p < 0.05). Logistic regression analysis identified that baseline waist-to-hip ratio (odds ratio [OR] = 1.71 [95% CI 1.08-2.69], p < 0.05) and elevated triglyceride (OR = 6.63 [95% CI 1.23-35.69], p < 0.05) are associated with the progression to T2DM in PCOS. Limitations of this study include moderate sample size with limited number of incident diabetes during follow-up period and potential selection bias.

Conclusions: High risk of diabetes and increased cardiovascular disease risk factors among Chinese women with PCOS are highlighted in this long-term follow-up study. Diabetes onset was, on average, 10 years earlier among women with PCOS than in women without PCOS.
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October 2019

Quantitation of paracetamol by liquid chromatography-mass spectrometry in human plasma in support of clinical trial.

Future Sci OA 2018 Sep 15;4(8):FSO331. Epub 2018 Aug 15.

Nuffield Department of Clinical Medicine, Centre for Tropical Medicine & Global Health, University of Oxford, Old Road campus, Roosevelt Drive, Headington, Oxford, OX3 7FZ, UK.

Aim: Paracetamol is a well-tolerated antipyretic widely used in severe malaria management. The study aimed to develop and validate a rapid LC-MS/MS assay to quantify paracetamol in plasma from patients with severe malaria.

Materials & Methods: Plasma sample was precipitated by organic solvent containing isotope-labeled paracetamol internal standard. Supernatant was isolated, diluted with water, followed by LC-MS/MS analysis.

Results: Plasma samples were extracted and assayed in less than 5.5 min. The assay response was linear (0.125-50 mg/l) with total intra- and interassay imprecision of <1.4%, which were considerably lower than most published reports.

Conclusion: We developed, validated and applied a rapid and small volume LC-MS/MS assay with high precision and accuracy for plasma paracetamol quantitation in 989 samples from 62 patients with severe malaria. The simple and high-throughput quality could facilitate assay automation for future clinical studies.
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September 2018

Methylmercury levels in commonly consumed fish and methylmercury exposure of children and women of childbearing age in Hong Kong, a high fish consumption community.

Environ Res 2018 10 22;166:418-426. Epub 2018 Jun 22.

Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR. Electronic address:

Background: Despite high fish consumption levels of Hong Kong residents, little is known about the MeHg exposure levels of Hong Kong high-risk populations (i.e. young children and women of childbearing age).

Objectives: To investigate the MeHg levels in fish commonly consumed in Hong Kong and assess the exposure levels of local kindergarten children and women of childbearing age.

Methods: A community-based survey was conducted in randomly recruited local kindergartens. The MeHg concentrations of the most commonly consumed fish items were measured. Based on their fish consumption data, subjects' MeHg exposure levels were estimated and compared with the reference dose (RfD) set by U.S. Environmental Protection Agency.

Results: A total of 2917 mother-child pairs were recruited. The MeHg levels of the fish samples ranged from < 2-1498.7 ng/g. Six frozen cod fish samples contained MeHg levels exceeding the local legal limit of 500 ng/g. The median estimated MeHg intake for children and mothers were 0.29 and 0.22 µg/kg bw/wk, respectively. Approximately 16% children and 9% mothers exceeded the RfD.

Conclusions: Apart from frozen cod fish, most fish species commonly consumed in Hong Kong had low MeHg content. Although the majority of our subjects were exposed to low MeHg levels, high fish consumers could still exceed the RfD and are potentially at risk of MeHg toxicity. To avoid excessive MeHg exposure, we suggest that young children and their mothers may consume a variety of locally available fish, but avoid consumption of frozen cod fish.
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October 2018

Parental history of depression and higher basal salivary cortisol in unaffected child and adolescent offspring.

J Affect Disord 2018 07 27;234:207-213. Epub 2018 Feb 27.

Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.

Introduction: There are contradictory findings regarding the associations of parental depression on the hypothalamic-pituitary-adrenal axis activity of their offspring. We aimed to explore the associations of parental depression on the diurnal salivary cortisol profile in their child and adolescent offspring.

Methods: A total of 189 unaffected child and adolescent offspring as determined by structured clinical interview were divided into 3 groups according to their parental history of depression, namely current parental depression (CPD, n = 27), past parental depression (PPD, n = 57), and no parental depression (NPD, n = 105). Diurnal saliva samples were collected to measure the cortisol awakening response and diurnal cortisol profile.

Results: CPD group had significantly higher basal cortisol level (mean ± SE = 11.9 ± 0.80 nmol/dl) than PPD group (mean ± SE = 9.7 ± 0.73 nmol/dl, post hoc p = .024) and NPD group (mean ± SE = 10.2 ± 0.52 nmol/dl, post hoc p = .031) and lower cortisol level at noon, but comparable cortisol levels in other time points. The cortisol awakening response reference to increase (AUCi) were significantly blunted in CPD group when compared with PPD and NPD (post hoc p < .01). Adjustment for potential confounding factors did not change major findings. Further analyses revealed that main influences were derived from current maternal depression.

Limitations: A single day of saliva sample.

Conclusion: Current but not past (lifetime) parental depression is associated with higher basal salivary cortisol and blunted cortisol awakening response in their children and adolescents.
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July 2018

Functional Ulnar Nerve Paraganglioma: First Documented Occurrence in the Extremity With Hitherto Undescribed Associated Extensive Glomus Cell Hyperplasia and Tumorlet Formation.

Int J Surg Pathol 2018 Feb 11;26(1):64-72. Epub 2017 Jul 11.

2 Prince of Wales Hospital, New Territory, Hong Kong.

Extra-adrenal paraganglioma has never been described in the extremities. A 34-year-old woman complained of an enlarging mass in the right forearm for 18 months. Imaging showed a circumscribed vascular tumor attached to the ulnar nerve; biopsy revealed features of paraganglioma. The resected tumor consisted of zellballen pattern of chief cells staining positively for chromogranin with surrounding S100-positive sustentacular cells. The chief cells contained many neurosecretory granules and mitochondria, whereas the sustentacular cells contained a large amount of rough endoplasmic reticulum and some microfilaments. There was adjacent extensive glomus cell hyperplasia and tumorlet formation. The intraoperative blood pressure dropped abruptly on tumor removal. The serum normetanephrine level decreased from a preoperative level of 1987 pg/mL (normal < 149 pg/mL) to normal after operation. The patient admitted on questioning to a history of paroxysmal attacks of transient palpitation, hand tremors, and sweating; imaging showed no evidence of tumor in other parts of the body, and there was no family history of similar tumor; she remained well 33 months after the operation. This occurrence of functional ulnar nerve paraganglioma with the hitherto undescribed associated glomus cell hyperplasia and tumorlet formation attests to the probable existence of normal sympathetic paraganglia in the extremity and their intimate functional relationship with glomus bodies.
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February 2018

In Utero Exposure to Maternal Hyperglycemia Increases Childhood Cardiometabolic Risk in Offspring.

Diabetes Care 2017 05 9;40(5):679-686. Epub 2017 Mar 9.

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong.

Objective: The objective of this study was to evaluate the effect of maternal hyperglycemia during pregnancy on cardiometabolic risk in offspring during early childhood.

Research Design And Methods: A total of 970 mothers who had joined the Hyperglycemia and Adverse Pregnancy Outcome study were reevaluated, together with their child born during the study period, 7 years after delivery.

Results: Offspring born to mothers diagnosed with gestational diabetes mellitus (GDM), as defined by the World Health Organization 2013 GDM criteria, had higher rates of abnormal glucose tolerance (4.7% vs. 1.7%; = 0.04), higher rates of overweight or obesity, greater BMI, higher blood pressure (BP), lower oral disposition index, and a trend toward reduced β-cell function compared with those born to mothers without GDM. For each SD increase in maternal fasting, 1-h, and 2-h glucose levels on oral glucose tolerance tests (OGTTs) between 24 and 32 weeks of the index pregnancy, the risk of abnormal glucose tolerance in the offspring showed a corresponding increase (adjusted odds ratio [OR] 1.85-2.00). The associations were independent of BMI before pregnancy, childhood obesity, or being born large for gestational age. The area under the curve for glucose levels during the five-point OGTT increased to a similar extent in boys and girls with each SD increase in maternal 1-h and 2-h plasma glucose on OGTTs during pregnancy. All three maternal glucose levels were also associated with increased adjusted ORs for childhood overweight or obesity and adiposity among girls, but not boys.

Conclusions: Maternal hyperglycemia in pregnancy is independently associated with offsprings' risk of abnormal glucose tolerance, obesity, and higher BP at 7 years of age. Its effect on childhood adiposity was apparent only in girls, not boys.
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May 2017

Serum Insulin-like Growth Factor I Quantitation by Mass Spectrometry: Insights for Protein Quantitation with this Technology.

EJIFCC 2016 Dec 1;27(4):318-330. Epub 2016 Dec 1.

Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital , Shatin, Hong Kong SAR, China.

Liquid chromatography mass spectrometry (LC-MS) is a widely used technique in the clinical laboratory, especially for small molecule quantitation in biological specimens, for example, steroid hormones and therapeutic drugs. Analysis of circulating macromolecules, including proteins and peptides, is largely dominated by traditional enzymatic, spectrophotometric, or immunological assays in clinical laboratories. However, these methodologies are known to be subjected to interfering substances, for example heterophilic antibodies, as well as subjected to non-specificity issues. In recent years, there has been a growing interest in using LC-MS platforms for protein analysis in the clinical setting, due to the superior specificity compared to immunoassay, and the possibility of simultaneous quantitation of multiple proteins. Different analytical approaches are possible using LC-MS-based methodology, including accurate mass measurement of intact molecules, protein digestion followed by detection of proteolytic peptides, and in combination with immunoaffinity purification. Proteins with different complexity, isoforms, variants, or chemical alteration can be simultaneously analysed by LC-MS, either by targeted or non-targeted approaches. While the LC-MS platform offers a more specific determination of proteins, there remain issues of LC-MS assay harmonization, correlation with current existing platforms, and the potential impact in making clinical decision. In this review, the clinical utility, historical aspect, and challenges in using LC-MS for protein analysis in the clinical setting will be discussed, using insulin-like growth factor (IGF) as an example.
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December 2016

Impact of fetal and childhood mercury exposure on immune status in children.

Environ Res 2016 Jan 9;144(Pt A):66-72. Epub 2015 Nov 9.

Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.

Background: Mercury exposure have been shown to affect immune status in animals as reflected by cytokine expression. It is unclear whether low levels of exposure during fetal and/or childhood periods could impact on immune status in humans.

Objectives: To test the hypothesis that fetal and childhood mercury exposure is associated with childhood cytokine profiles and to investigate whether childhood selenium levels interact with any of the associations found.

Methods: Children were recruited from a previously established birth cohort between the ages of 6-9 years for assessment and measurement of blood mercury, selenium and cytokine profile (interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13 and TNF-alpha). Multivariable linear regression models were used to assess the adjusted association of cord blood mercury concentration and current mercury concentrations with levels of the cytokine levels. We tested whether the association with current mercury level varied by current selenium level and cord blood mercury level.

Results: IL-10 was negatively associated with current blood mercury concentration. The effect was greatest in cases with low cord blood mercury and low current selenium concentrations. None of the other cytokine levels were associated with either cord blood or current blood mercury concentrations, except that cord blood mercury was negatively associated with IL-6.

Conclusions: Childhood mercury exposure was negatively associated with childhood IL-10 levels. It is postulated that while selenium is protective, low levels of fetal mercury exposure may increase the degree of this negative association during childhood. Further studies into the clinical significance of these findings are required.
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January 2016

Circulating bacterial-derived DNA fragment level is a strong predictor of cardiovascular disease in peritoneal dialysis patients.

PLoS One 2015 26;10(5):e0125162. Epub 2015 May 26.

Carol & Richard Yu Peritoneal Dialysis Research Centre, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Background: Circulating bacterial DNA fragment is related to systemic inflammatory state in peritoneal dialysis (PD) patients. We hypothesize that plasma bacterial DNA level predicts cardiovascular events in new PD patients.

Methods: We measured plasma bacterial DNA level in 191 new PD patients, who were then followed for at least a year for the development of cardiovascular event, hospitalization, and patient survival.

Results: The average age was 59.3 ± 11.8 years; plasma bacterial DNA level 34.9 ± 1.5 cycles; average follow up 23.2 ± 9.7 months. At 24 months, the event-free survival was 86.1%, 69.8%, 55.4% and 30.8% for plasma bacterial DNA level quartiles I, II, III and IV, respectively (p < 0.0001). After adjusting for confounders, plasma bacterial DNA level, baseline residual renal function and malnutrition-inflammation score were independent predictors of composite cardiovascular end-point; each doubling in plasma bacterial DNA level confers a 26.9% (95% confidence interval, 13.0 - 42.5%) excess in risk. Plasma bacterial DNA also correlated with the number of hospital admission (r = -0.379, p < 0.0001) and duration of hospitalization for cardiovascular reasons (r = -0.386, p < 0.0001). Plasma bacterial DNA level did not correlate with baseline arterial pulse wave velocity (PWV), but with the change in carotid-radial PWV in one year (r = -0.238, p = 0.005).

Conclusions: Circulating bacterial DNA fragment level is a strong predictor of cardiovascular event, need of hospitalization, as well as the progressive change in arterial stiffness in new PD patients.
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February 2016

Plasma natriuretic peptides in children and adolescents with obstructive sleep apnea and their changes following intervention.

Front Pediatr 2014 24;2:22. Epub 2014 Mar 24.

Department of Psychiatry, Shatin Hospital, The Chinese University of Hong Kong , Hong Kong , China.

Objective: This study aimed to evaluate circulating natriuretic peptides (NP) concentration in obese and non-obese children and adolescents with and without obstructive sleep apnea (OSA), and their levels following OSA treatment.

Methods: Subjects with habitual snoring and symptoms suggestive of OSA were recruited. They underwent physical examination and overnight polysomnography (PSG). OSA was diagnosed if obstructive apnea-hypopnea index (OAHI) was ≥1/h. Fasting serum atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were taken after overnight PSG. The subjects were divided into obese, non-obese, with and without OSA groups for comparisons.

Results: One hundred fourteen children (77 were boys) with a median [interquartile range (IQR)] age of 10.8 (8.3-12.7) years (range: 2.4-11.8 years) were recruited. Sixty-eight subjects were found to have OSA. NP levels did not differ between subjects with and without OSA in both obese and non-obese groups. Stepwise multiple linear regressions revealed that body mass index (BMI) z-score was the only independent factor associated with NP concentrations. Fifteen children with moderate-to-severe OSA (OAHI >5/h) underwent treatment and there were no significant changes in both ANP and BNP levels after intervention.

Conclusion: Body mass index rather than OSA was the main determinant of NP levels in school-aged children and adolescents.
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April 2014

Urinary biomarkers for the prediction of reversibility in acute-on-chronic renal failure.

Dis Markers 2013 ;34(3):179-85

Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Background: There is no reliable clinical test to predict the reversibility of acute-on-chronic renal failure. We study whether urinary biomarkers could be used as a noninvasive prognostic marker in patients with acute-on-chronic renal failure.

Methods: We studied 39 adult patients with pre-existing chronic renal impairment presenting to us with acute-on-chronic renal failure. Urinary neutrophil gelatinase-associated lipocalin (NGAL) level was measured. The mRNA of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), alpha-1-microglobulin (α1M), sodium/hydrogen exchanger-3 (NHE3), beta-2 microglobulin (β2M), and N-acetyl-β-D-glucosaminidase (NAG) in urinary sediment were quantified.

Results: Urinary NGAL level significantly correlated with the serum creatinine at presentation (r=0.762, p<0.0001) but not baseline serum creatinine. Urinary sediment β2M expression significantly correlated with baseline glomerular filtration rate (GFR) (r=−0.400, p=0.012). Urinary α1M and NHE3 expressions were significantly higher in ischemic acute tubular necrosis than other causes of acute kidney injury (p<0.0001 and p=0.006, respectively). Urinary α1M expression significantly correlated with the degree of improvement in renal function (r=0.387, p=0.026), as well as the estimated GFR 6 months later (r=0.386, p=0.027).

Conclusion: In patients with acute-on-chronic renal failure, urinary NGAL level correlates with the severity of renal failure, while urinary α1M expression correlates with the degree of renal function recovery. Quantification of urinary α1M mRNA may be developed as an non-invasive tool for risk stratification of this group of patients.
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July 2013

Prediction of women's long-term cardiometabolic risks using glycemic indices during pregnancy.

J Obstet Gynaecol Res 2013 Feb 13;39(2):484-91. Epub 2012 Aug 13.

Departments of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.

Aims: To study the prediction of abnormal glucose tolerance (AGT), diabetes mellitus (DM), hypertension (HT) and metabolic syndrome (MetS) among Chinese women using glycemic indices in the mid-trimester of pregnancy.

Methods: A cohort of Chinese women who had had either normal glucose tolerance or gestational diabetes mellitus (GDM) during a pregnancy were assessed at a median of 8 and 15 years post-delivery. All women underwent a 50-g glucose challenge test (GCT) and a 75-g oral glucose tolerance test in the mid-trimester of the index pregnancy. A receiver operating characteristic curve was used to assess the prediction of AGT, DM, HT and MetS.

Results: All glycemic indices were significant predictors of AGT and DM, and the 2-h plasma glucose (PG) and GCT were predictive of HT, at both 8 and 15 years post-delivery. MetS can only be predicted by the fasting plasma glucose (FPG) and was confined to 15 years post-delivery. After adjustment for confounding variables, all glycemic indices were still independent predictors of AGT and DM at both 8 and 15 years post-delivery, except for FPG in predicting DM at 8 years, while only the 2-h PG remains an independent predictor of HT at 15 years. The optimal cut-off values for FPG, 2-h PG and GCT are 4.2 mmol/L, 7.2 mmol/L and 7.7 mmol/L, respectively; all are lower than the current cut-off thresholds for the screening and diagnosis of GDM.

Conclusions: Women who had a glycemic level below the criteria for a positive screening test and below the diagnostic threshold for GDM still have a significant cardiometabolic risk.
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February 2013

Cardiometabolic risk in Chinese women with prior gestational diabetes: a 15-year follow-up study.

Gynecol Obstet Invest 2012 16;73(2):168-76. Epub 2011 Dec 16.

Departments of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, SAR, China.

Aims: The progression to type 2 diabetes mellitus (DM) and other long-term cardiometabolic risks in Chinese women with prior history of gestational diabetes (GD) was studied at 15 years postpartum.

Methods: 139 Chinese women (45 with GD and 94 with normal glucose tolerance (NGT) at the index pregnancy) who had their insulin sensitivity and β-cell functions examined at 8 years postpartum were again followed up at 15 years for the investigation of the rate of type 2 DM, hypertension and metabolic syndrome.

Results: Women with prior history of GD had a significantly higher rate of hypertension (35.6% vs. 16.0%, p = 0.01), type 2 DM (24.4% vs. 5.3%, p < 0.001) and impaired glucose regulation (26.6% vs. 14.9%, p < 0.001) than women with NGT during the index pregnancy. The Matsuda insulin sensitivity index and the quantitative insulin sensitivity check index at 8 years postpartum were independent predictors of both DM and metabolic syndrome at 15 years postpartum.

Conclusions: The conversion rate of type 2 DM increased at an average rate of 1.6% per year after a pregnancy affected by GD. Insulin resistance at 8 years postpartum could refine a future diabetic risk in women with prior history of GD.
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August 2012

Familial aggregation of narcolepsy.

Sleep Med 2011 Dec 28;12(10):947-51. Epub 2011 Oct 28.

Department of Psychiatry, The Chinese University of Hong Kong, Shatin, Hong Kong.

Objectives: To determine the familial aggregation of narcolepsy from perspectives of clinical symptomatology, polysomnographic data, and human leukocyte antigen (HLA) typing.

Methods: This was a Family study at the University-affiliated hospital. The participants were narcolepsy probands and their first degree relatives, and, also, age and sex matched unrelated healthy controls. Interventions were not applicable.

Measurements And Results: All study subjects underwent structured interviews, overnight polysomnography followed by a multiple sleep latency test (MSLT), and HLA typing. Altogether, 33 probands and 81 first degree relatives (response rate 65%) were recruited. Among the relatives, 12.3% were diagnosed with narcolepsy and 39.5% had narcolepsy spectrum as defined by unexplained abnormal MSLT (shortened MSL and SOREMP) results. The relative risk of narcolepsy in first degree relatives was 361.8. Familial aggregation of narcolepsy symptoms, excessive daytime sleepiness, HLA status, abnormal MSLT, and nocturnal polysomnographic findings were observed.

Conclusions: The familial risk of narcolepsy among first degree relatives is much higher than previously reported. There exists a spectrum of narcolepsy features among relatives, ranging from full clinical tetrads to asymptomatic abnormal MSLT findings.
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December 2011

The reproductive and metabolic effect of rosiglitazone on Chinese women with polycystic ovarian syndrome--a double-blind randomized placebo-controlled study.

Fertil Steril 2011 Aug 1;96(2):445-451.e1. Epub 2011 Jul 1.

Department of Obstetrics and Gynecology, Prince of Wales Hospital, Hong Kong, People's Republic of China.

Objective: To investigate whether an insulin sensitizer has any effect on amenorrhea and clinical and biochemical hyperandrogenism in Chinese women with polycystic ovarian syndrome (PCOS).

Design: Randomized controlled double-blind trial.

Setting: A tertiary referral center, Hong Kong.

Patient(s): Chinese women who fulfilled the Rotterdam criteria of PCOS (n = 70).

Intervention(s): Rosiglitazone 4 mg daily for the first month followed by 4 mg twice daily for 11 months.

Main Outcome Measure(s): Menstrual status as well as clinical and biochemical hyperandrogenism.

Result(s): There is a significantly higher rate of regular menses among the treatment arm (16 [50.0%] of 32 vs 4 [11.8%] of 34) at 6 months and the improvement appeared to be sustained (10 [41.7%] of 24 vs 6 [20.0%] of 30) at 12 months. There was no change in the acne and hirsutism scores as well as serum T levels in both arms.

Conclusion(s): We found a possible benefit in menstrual cyclicity but a lack of improvement in hyperandrogenism in our Chinese population.

Clinical Trial Registration Number: ChiCTR-TRC-09000670 (Chinese Clinical Trial Registry).
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August 2011

Gestational and lactational transfer of melamine following gavage administration of a single dose to rats.

Food Chem Toxicol 2011 Jul 30;49(7):1544-8. Epub 2011 Mar 30.

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

Melamine contamination in an infant formula manufactured by a firm in China was reported in September 2008. Maternal transfer of melamine during pregnancy and through breast-feeding are possible ways of introduction. This study aims to evaluate the maternal transfer of melamine into amniotic fluid and breast milk through oral intake by pregnant and lactating rats, respectively. The quantity of melamine in the dam's sera, amniotic fluid, breast milk as well as in fetal whole body extract was measured. Our results showed that, after administration of single dose of 21.4 mg/kg per body weight of melamine to pregnant rats (16-18 days of gestation) by gavage, about 80% of melamine was found in dam's serum in 0.5 h. Melamine further reached the fetuses through placental transfer as it was found that peak melamine level of 7.15 ppm (∼30%) was detected in the fetuses after 2h and 4.36 ppm (∼20%) was shown in amniotic fluid after 3h of maternal intake. In the lactating rats, about 40% of maternal intake of melamine was transferred to breast milk and peaked at 3h. The results of this study confirmed the maternal transfer of melamine to fetuses in utero and infants through breast feeding.
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July 2011

Glucose intolerance and cardiometabolic risk in adolescents exposed to maternal gestational diabetes: a 15-year follow-up study.

Diabetes Care 2010 Jun 9;33(6):1382-4. Epub 2010 Mar 9.

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR.

Objective: Adolescent offspring of women with a history of gestational diabetes (GD) were evaluated for their cardiometabolic risks at a mean age of 15 years.

Research Design And Methods: One hundred and twenty-nine adolescents who were assessed for their cardiometabolic risks at 8 years of age were reassessed at 15 years of age.

Results: Adolescent offspring of mothers with GD had similar blood pressure, plasma lipid profile, and a rate of abnormal glucose tolerance as control subjects. In utero hyperinsulinemia was associated with a 17-fold increase in metabolic syndrome and a 10-fold increase in overweight at adolescence, independent of birth weight, Tanner stage, maternal GD status, and mother's BMI.

Conclusions: In utero environment of hyperinsulinemia, irrespective of the degree of maternal GD, was associated with increased risk of overweight and metabolic syndrome during early adolescence in the offspring.
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June 2010

Comparison in the performance of glucose meters in blood glucose monitoring during pregnancy.

Gynecol Obstet Invest 2010 21;69(4):264-9. Epub 2010 Jan 21.

Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Hong Kong, SAR, China.

Aims: To compare the performance of the four latest models of glucose meters in capillary blood glucose monitoring during pregnancy.

Methods: 208 pregnant women with gestational diabetes were recruited. Each subject had simultaneous capillary glucose monitoring by two study glucose meters and venous plasma glucose assay. The performance of four glucose meters was compared using error grid analysis (EGA) and the agreement between the meter readings and plasma glucose by Bland-Altman plot analysis.

Results: Elite, Advantage II and CareSens had more than 90% of readings in the acceptable target range of EGA. CareSens had the lowest mean bias by Bland-Altman analysis while Advantage II had the highest proportion of readings within 5% difference from plasma glucose. Readings from all glucose meters except Optium were not influenced by the change in maternal hematocrit levels.

Conclusions: The performance of four study glucose meters appeared very similar.
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September 2010

DNA-based diagnosis of malignant osteopetrosis by whole-genome scan using a single-nucleotide polymorphism microarray: standardization of molecular investigations of genetic diseases due to consanguinity.

J Hum Genet 2007 11;52(1):98-101. Epub 2006 Oct 11.

Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.

Malignant osteopetrosis, a severe disease causing early infantile death in humans, is caused by mutations in the TCIRG1, CLCN7, or OSTM1 genes. We have established the molecular basis of malignant osteopetrosis in a Chinese family by means of whole-genome scans based on high-density single-nucleotide polymorphism (SNP) microarrays. Because the parents were consanguineous, the disease-causing locus should be located in an autozygous chromosomal region. Mapping revealed that among the three possible causal loci, only the CLCN7 gene was located in an autozygous region. Mutational analysis of the CLCN7 gene showed that the proband was homozygous for a novel missense mutation, p.I261F. p.I261 is located in helix F of the chloride channel, near a critical site for gating of the channel. This mapping study prepares the ground for future mutation studies by decreasing the burden of completely sequencing all possible loci for this disease. This approach can be used to standardize molecular investigations of genetic diseases due to consanguinity to a whole-genome scan and subsequent sequencing of the mapped disease gene.
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March 2007

Risk factors of vitamin B(12) deficiency in patients receiving metformin.

Arch Intern Med 2006 Oct;166(18):1975-9

Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin, Hong Kong.

Background: Identification of risk factors for metformin-related vitamin B(12) deficiency has major potential implications regarding the management of diabetes mellitus.

Methods: We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B(12) and hemoglobin A(1c) checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B(12) deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B(12) deficiency while taking metformin.

Results: A total of 155 patients with metformin-related vitamin B(12) deficiency (mean +/- SD serum vitamin B(12) concentration, 148.6 +/- 40.4 pg/mL [110 +/- 30 pmol/L]) were compared with 310 matched controls (466.1 +/- 330.4 pg/mL [344 +/- 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B(12) deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B(12) deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P = .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B(12) concentration, dose of metformin remained the strongest independent predictor of vitamin B(12) deficiency.

Conclusions: Our results indicate an increased risk of vitamin B(12) deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.
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October 2006

A whitened face woman with nephrotic syndrome.

Am J Kidney Dis 2003 Jan;41(1):250-3

Department of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Skin whitening cream from developing countries is a recognized source of chronic mercury poisoning. The authors report on a 34-year-old Indonesian domestic helper who presented with nephrotic syndrome secondary to membranous nephropathy. It was subsequently found that she used a skin whitening cream regularly that was found to contain a mercury level of almost 2,000 times above the allowable limit. Her blood and urinary mercury levels were both grossly elevated. Her symptoms improved after she stopped using the cream. However, she returned to her home country before chelating therapy could be arranged. Because mercury-containing skin products are still widely available in developing countries, the use of these products should be considered a possible cause of membranous nephropathy in immigrants from those countries.
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January 2003