Proceedings of Congress
Joint Annual Scientific Meeting 2013 - Oral Presentation (Doctor's Session)
Intranasal Corticosteroids for Mild Childhood Obstructive Sleep Apnoea - A Randomised Placebo-Controlled Study
KC Chan, CT Au, HS Lam, AM Li
Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
Background: Background Childhood obstructive sleep apnoea (OSA) is prevalent and if untreated could lead to significant cardiovascular and neurocognitive complications. Although adenotonsillectomy remains the first-line treatment of childhood OSA, it has its limitations and risks. Use of non-surgical treatment is gaining popularity especially in children with mild OSA.
Objective: To test the hypothesis that topical intranasal corticosteroids would decrease the severity of mild OSA in children.
Methods: We conducted a randomized, double-blinded, placebo-controlled trial of intranasal mometasone furoate (MF) versus placebo in children aged 6 to 18 years with mild OSA (apnoea hypopnoea index (AHI) between 1 and 5) proven on polysomnography (PSG). The medication / placebo were taken once daily. The primary outcome was the change from baseline AHI as documented by overnight PSG after a 4-month treatment. The secondary outcomes included the change from baseline (1) tonsil and adenoid size and (2) nasal symptoms.
Results: 62 children (mean age±SD = 11.1±2.8) were recruited. Thirty one received MF and 31 received placebo. AHI and oxygen desaturation index (ODI) were significantly reduced only in the MF group. The AHI decreased from 2.7±0.2 to 1.7±0.3 in the MF group but increased from 2.5±0.2 to 2.9±0.6 in the placebo group (p=0.039). The mean change in ODI in the MF group and placebo group were -0.6?.5 and +0.7?.4 respectively (p=0.037). The proportion of children having habitual snoring was also reduced in the MF group, from 75% to 54.5% (p=0.031), but not in the placebo group. Changes from baseline in tonsil and adenoid size, and daytime nasal symptoms were not significantly different between groups.
Conclusion: A 4-month treatment with intranasal mometasone furoate effectively reduced the severity of mild OSA in children. These findings justify the use of topical steroids as an initial therapeutic option in children with mild OSA.
Prevalence of Vitamin D Insufficiency Among Adolescent Girls in Hong Kong and Its Correlations with Dxa Parameters
TF Cheung,1 WS Yu,1 TP Lam,1 FWP Yu,1 WY Mak,1, VWY Hung,1 CS Ho,2 BKW Ng,1 KM Lee,3 L Qin,1, JCY Cheng1
1Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong; 2Department of Chemical Pathology, The Chinese University of Hong Kong; 3Lee Hysan Clinical Research Laboratories, The Chinese University of Hong Kong, Hong Kong
Objectives: Vitamin D (Vit-D) is essential for bone homeostasis but the relationship between Vit-D status and areal bone mineral density (aBMD) remains inconclusive especially in adolescent population. The aims of this study were to evaluate the Vit-D status and its correlation with BMD parameters among adolescent girls in Hong Kong.
Methods: 248 adolescent girls (11.5-16.5 years old) were recruited separately in both summer (June to September, N=124) and winter (December to March, N=124). Bone mineral content (BMC) and aBMD of bilateral femoral necks were measured by dual-energy
X-ray absorptiometry (DXA). Serum 25(OH)Vit-D and PTH level were measured by liquidchromatography- tandem mass-spectrometry and immunoassay respectively. Dietary calcium intake and physical activity level were assessed by validated food frequency questionnaire and modified Beacke questionnaire respectively. Multivariate linear regression analysis was applied to detect any correlation between DXA parameters and serum 25(OH)Vit-D levels.
Result: Mean serum 25(OH)Vit-D level in summer was significantly higher than that in winter (44.6±12.2 nmol/L and 34.4±9.9 nmol/L, p<0.001). Prevalence of Vit-D insufficiency [25≤25(OH)Vit-D≤50 nmol/L] in summer and winter were 60.5% and 76.6% respectively while the prevalence of Vit-D deficiency [25(OH)Vit-D<25 nmol/L] was 4.0% and 15.3% respectively. The prevalence of Vit-D insufficiency and deficiency were significantly higher in winter (p<0.001). Serum PTH level in summer was significantly lower than that in winter (5.15±3.16 pmol/L and 6.16±3.79 pmol/L, p<0.05). In multiple linear regression analysis, after adjustment for age, BMI, Tanner staging, physical activity level, dietary calcium intake and season, the positive correlations between 25(OH)Vit-D and both dominant and nondominant femoral neck aBMD and BMC were statistically significant. In season-specific model, positive correlations between 25(OH)Vit-D and both dominant and non-dominant femoral neck aBMD and BMC were significant in summer while no significant correlations could be detected in winter.
Conclusions: Although Hong Kong is a subtropical city at latitude of 22°N with sufficient sunshine, the prevalence of Vit-D insufficiency and associated low femoral BMD were still high among adolescent girls. This important bone health issue can be a significant public health concern. Further studies to investigate possible association between lifestyle factors and related therapeutic measures targeted on Vit-D insufficiency are warranted.
Acknowledgments: The project was funded by General Research Fund, University Grants Council of Hong Kong (Project number: 468411, 468809).
Quality of Life and Psychosocial Issues Are Important Outcome Measures in Eczema Treatment
KL Hon, H Poon, T Poon, TF Leung
Department of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, hong Kong
Background: Atopic eczema (AE) is a common relapsing inflammatory skin disease in children associated with chronicity and poor quality of life (QoL). Many children also display depressive, anxiety and stress symptoms.
Aim: To investigate the prevalence of depressive, anxiety and stress symptoms, and if these symptoms are associated with disease severity, QoL and skin biophysiology in childhood AE.
Methods: Psychological symptoms, eczema severity, QoL and biophysical skin condition of consecutive adolescents at the pediatric dermatology clinic of a teaching hospital were evaluated with the validated Chinese versions of Depressive, Anxiety, Stress Scales (DASS-42), Beck Depression Inventory (BDI-13), Nottingham Eczema Severity Score (NESS), Children's Dermatology Life Quality Index (CDLQI), transepidermal water loss (TEWL), and stratum corneum skin hydration (SH), respectively.
Results: AE patients (n=120) had lower SH, higher TEWL, worse CDLQI, and reported higher prevalence of depressive, anxiety and stress symptoms, personal history of atopy, current topical corticosteroid usage and food avoidance than non-AE patients (n=25) (Table 1). Depressive, anxiety and stress symptoms were reported in 21%, 20% and 42% of AE patients, respectively. Multivariate analyses showed that these symptoms were significantly correlated with a poor QoL (partial correlations of 0.40-0.49; p<0.001) (Figure 1). Male patients had more severe disease (higher NESS, p=0.036) and DASS-depressive symptoms (multivariate OR=3.2, p=0.034) than females. Patients who reported current topical steroid usage generally practiced food avoidance (p=0.047), had poor quality of life (p=0.043) but less DASS-depression (multivariate OR=0.354, p=0.043). Only 6% of the 120 AE patients reported prior psychology consultation.
Conclusions: Quality of life impairments correlate with disease severity, aberrant skin biophysiology, depression, anxiety and stress symptoms in adolescents with AE. Physicians caring for these patients must evaluate the different but inter-correlated medical, biophysiological and pertinent psychosocial domains. These significant correlations imply that a holistic approach should encompass psychotherapy, behavioral therapy and coping strategies in conjunction with dermatologic therapy.
Effects of Histone Deacetylase Inhibitor and Proteasome Inhibitor on Epstein-Barr Virus-Positive Burkitt Cells and Lymphoblastoid Cell Lines
YY Leung, KF Hui, AKS Chiang
Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
Background: Both histone deacetylase inhibitors (HDACis) and proteasome inhibitors have been shown to be capable of mediating cytotoxic effects in Epstein-Barr virus (EBV)-positive lymphomas. EBV can establish latent infections with different latent gene expression patterns. In latency I pattern of viral infection, only EBNA1 and EBERs are expressed, whereas in latency III pattern, all of the EBV latent genes including EBNA-1, -2, -3A, -3B, -3C, - LP, LMPs and EBERs are expressed. In Wp-restricted latency pattern, all of the latent genes are expressed in the absence of EBNA2 and LMPs. It is known that EBV latent gene expression protects lymphoma cells from apoptosis. We hypothesised that EBV infected cells with different EBV latency patterns would have differential responses to the treatment with HDACis or proteasome inhibitors. In this study, we aim to investigate the effects of HDACi (suberoylanilide hydroxamic acid), proteasome inhibitor (bortezomib) and their combination on a panel of EBV-positive burkitt lymphoma (BL) cells and lymphoblastoid cell lines (LCLs) with different patterns of EBV latency.
Methods: Cytotoxic effects of SAHA, bortezomib and their combination on BL cells, including latency I (Akata 2003, Mutu-I), Wp-restricted (Daudi, P3HR1-c16), latency III (Raji, Mutu-III and LCLs) were determined by MTT assay. Apoptosis and cell cycle were measured by flow cytometry. Expression of apoptotic markers, acetylation of histone and EBV latent proteins were determined by western blot analysis.
Results: Either SAHA or bortezomib alone inhibited proliferation of EBV-positive BL cells and LCLs. BL cells with Wp-restricted or type III latency pattern were more resistant to killing by SAHA or bortezomib alone than those BL cells with standard type I latency. Interestingly, combination of SAHA and bortezomib synergistically enhanced the killing of Wp-restricted or latency III BL cells. Substantial increase in Annexin V-positive and sub-G1 were observed in these cell populations. Further, the drug combination enhanced proteolytic cleavage of PARP, activation of caspase-3 & 9 and acetylation of histone when compared with either drug alone. Furthermore, combination of SAHA and bortezomib suppressed the growth of BL xenografts in nude mice. The resistance to either SAHA or bortezomib alone and enhanced apoptosis by combining bortezomib and SAHA could also be observed in LCLs which express a full set of EBV latent genes. Further examination of the expression pattern of EBV latent proteins indicated that EBNA3A, rather than EBNA1, EBNA2 or LMP1, contributed to the resistance to the single drug treatments.
Conclusions: Expression of EBV latent genes in Wp-restricted and latency III infected cells confers resistance to treatment with SAHA and bortezomib. Bortezomib could potentiate SAHA induced apoptosis of EBV-positive BL cells and LCLs expressing more EBV latent genes. Further investigation of the drug combination regimen for the treatment of BL cells is warranted.
This work forms part of the MPhil thesis of YY Leung and is funded by CRCG grant #104001264 and Epstein-Barr virus research grant (#20004525) of AKS Chiang.
Unveiling The Genetics of Long QT Syndrome: A Local Paediatric Experience
APY Liu,1 TC Yung,2 AKT Chau,2 Bhy Chung,1,3
1Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Li Ka Shing Faculty of Medicine, The University of Hong Kong; 2Department of Paediatric Cardiology, Queen Mary Hospital; 3Department of Obstetrics & Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
Long QT syndrome (LQTS) is the most common form of Sudden Arrhythmia Death Syndrome (SADS) with a prevalence of 1 in 2,500 individuals. Conventional diagnosis is based on case history, family history and ECG evaluation. Since 1996, thirteen LQTS genes have been discovered and current guidelines recommend that genetic testing should be incorporated as part of standard assessment in patients with suspected LQTS. The genotypes of our local cohort, is however, unknown. We recruited all the patients diagnosed with LQTS from the Department of Paediatric Cardiology of Queen Mary Hospital and offered genetic testing. Sequencing and MLPA were performed on 6 LQTS genes (LQT1-3, 5-7) by the Victorian Clinical Genetic Services to identify disease-causing mutations. A total of 19 patients were identified, 9 were male, with the QTc ranging from 460-619 ms. Mode of presentation included syncope (n=9), ventricular tachycardia (n=2), convulsion (n=1) and as incidental finding (n=7). Thirteen patients have been treated with b-blockers, one received mexiletine and ICD insertion, one was treated with a combination of mexiletine, propranolol and ICD insertion. Pathogenic mutations were identified in 9 patients (LQT1=3, LQT2=4, LQT3=1, LQT5=1), likely pathogenic mutations in 2 (LQT2), unclassified variants in 2, and no mutation in 6. Patients with pathogenic and likely pathogenic mutations had significantly longer mean QTc than those without such mutations (p=0.046). Three mutations, all in the LQT2 genes, represented novel mutations. All 3 patients with mutations in the porelooping forming domains of the KCNH2 (LQT2) channel had personal or family histories of malignant arrhythmia or sudden cardiac death compatible with previously reported genotype-phenotype correlation. The cost per positive genotype was approximately HK$47,000. Eight families involving 18 family members underwent cascade testing, and family mutations were identified in 10 individuals from 6 families. Autosomal dominant transmission was the likely mode of inheritance in these 6 families. Genetic testing is useful in diagnosis, prognostication and family screening in patients with LQTS, and should be offered to all patients with such condition. Future research direction would involve the use of next-generation sequencing techniques especially for mutation negative patients.
Regulation of HIV-Tat Induced Cytokine Expression and Consequent Opportunistic Infection by The Proto-Oncogene c-Myc
JCH Pong, JCB Li, ASY Lau
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong
Human immunodeficiency virus (HIV) remains a major health problem around the globe, especially in third world countries where acquired immunodeficiency syndrome (AIDS) is highly prevalent and currently incurable. The HIV-1 trans-activator (Tat) protein is an important viral protein that is known to contribute to the AIDS pathogenesis via the dysregulation of cytokines such as TNF-α and IL-6. In this study, we recognised that c-Myc, a proto-oncogene known to regulate a wide range of cellular process, also regulated primary blood derived macrophage (PBMac) immune response induced by HIV-1 Tat. We first found that HIV-1 Tat could induce the expression of c-Myc.The function and expression of HIV- 1 Tat induced c-Myc was subsequently found to be regulated through the activation of the dsRNA-activated protein kinase (PKR), ERK1/2 and p38 mitogen-activated protein kinase (MAPK). Inhibition of c-Myc expression in turn demonstrated that c-Myc may be essential for the up-regulation of the pro-inflammatory cytokines TNF-α and IL-6 by HIV-1 Tat. Furthermore, c-Myc regulation of HIV-1 Tat induced cytokine expression consequently affected the intracellular survival of the opportunistic microbe, Mycobacteria avium intracellulare, in PBMac. Taken together, we demonstrated that c-Myc may play a significant role in the pathogenesis of AIDS, by mediating the dysregulation of cytokine expression induced by Tat and possibly accentuate opportunistic infection.
Outcome of Hepatobiliary Scanning: Preterm Versus Full-Term Cholestatic Infants
LY Siu,1 KN Wong,2 KW Li,1 NS Kwong1
Department of Paediatrics, 1Tuen Mun Hospital; 2Hong Kong Sanatorium & Hospital, Hong Kong
Objectives: The aims of this study were to evaluate the specificity of a non-draining hepatobiliary scintigraphy (HBS) for biliary atresia (BA) in preterm and full-term babies, to verify the relationship between non-draining scan and higher levels of direct bilirubin and to find an objective criterion to guide the time in performing HBS.
Methods: A total of 175 infants (113 males and 62 females, median age of 45 days) with 181 HBS performed in Tuen Mun Hospital between January 1998 and May 2010 were retrospectively analysed. A "non-draining" scan was defined as one showing no excretion of radiolabelled tracer into the small bowel 24h after injection. The disease category, epidemiological and laboratory data were compared between infants having non-draining and draining scans. In addition, the predictive value of a negative scan for BA was compared between preterm and full-term infants.
Results: Twenty infants (11.4%) were surgically confirmed to have BA. A non-draining scan was found to be 100% sensitive for BA, and the specificity was 96% and 78% among full-term infants and preterm infants, respectively. The mean direct bilirubin values of infants with BA and intrahepatic cholestasis were 141.9 and 111.3 μmol/L, respectively, which were significantly higher than 67.2 μmol/L seen in infants with draining scans. This analysis shows that using direct bilirubin ≥63 μmol/L as an objective criterion in guiding the time to perform HBS is most cost-effective.
Conclusion: Our data supported that using direct bilirubin ≥63 μmol/L as an objective criterion in guiding the time to perform HBS will avoid unnecessary scans.
Integration of Chromosomal Microarray into Paediatric Clinical Care in Hong Kong
V Tao,1 W She,1 YY Chu,1 W Tso,1 KY Chan,2 EY Lau,2, A Kan,2 MH Tang,2 YL Lau,1 BHY Chung1,2
1Department of Paediatrics & Adolescent Medicine; 2Department of Obstetrics & Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
Chromosomal microarray (CMA) has emerged as a major tool to identify unbalanced chromosomal aberrations in children and is recommended as the first tiered investigation for intellectual disability, autism spectrum disorders and multiple congenital anomalies. While the clinical interpretation and genetic counseling remain as ongoing challenge, data about potential downstream benefits and harms of CMA is lacking, especially in paediatric population. Our objective is to evaluate the clinical impact of CMA on medical management in children. In 2011-2012, we performed high resolution CMA using the NimbleGen 135k oligonucleotide array on 240 children in a university-affiliated paediatric unit in Hong Kong. By retrospective chart review, descriptive and multivariate analyses are performed to understand the association between CMA results and change in the medical management. The detection rate of pathogenic/probably pathogenic chromosomal aberrations is 20% in our cohort. While detailed analysis is underway, it is clear that CMA detects chromosomal changes missed by karyotype in some patients, while in others it provides significant information in addition. Importantly these findings can be medically actionable and/or have major implications for family members. The insights we have learned from some of our patients have wider implications for the medical community e.g. the recommendation of cardiac assessment for patients with 17p13.3 duplication (Eur J Med Genet 2012; 55(12):758-62) and renal surveillance for patients with Xq22.3 deletion (Esophagus, in press), and have resulted in publications in peer-reviewed journals. One family with a neurodevelopmental phenotype and a probably pathogenic CMA finding has decided not to receive any further information as the parents realised that "knowing more may not be better". The potential of CMA findings to impact,
positively and negatively, on patients is tremendous and warrants careful evaluation. Our findings will be instructive in anticipating the impact of whole genomic analyses on medical management and downstream utilisation of health services.
Orlistat Improves Endothelial Function in Obese Adolescents: A Randomised Trial
CCW Yu,1,2 AM Li,2 KOW Chan,1 P Chook,2 JTC Kam,1 CT Au,2 RCH So,3 RYT Sung,2 AM McManus1
1Institute of Human Performance, The University of Hong Kong; 2Department of Paediatrics, The Chinese University of Hong Kong; 3Hong Kong Sports Institute, Hong Kong
Aim: To investigate the effect of orlistat on endothelial function in obese adolescents.
Methods: Single-blind 10-week controlled trial of sixty-seven normolipidaemic obese adolescents randomised into three groups. Group 1 (diet alone), Group 2 (diet and orlistat), Group 3 (diet, orlistat, and exercise). Endothelial function measured by flow-mediated dilatation (FMD) of the brachial artery, anthropometric parameters, blood pressure, fasting blood lipids, insulin and glucose levels were recorded at baseline and at 10-weeks.
Results: Sixty-four subjects completed the study. Groups were comparable at baseline. FMD increased significantly with orlistat (groups 2 and 3) but not in Group 1. Orlistat treatment resulted in significantly reduced body weight, BMI, waist circumference, total and LDL cholesterol levels. HDL-cholesterol levels were unchanged. Triglyceride and insulin levels were significantly reduced in all three groups. The reduction in cholesterols did not correlate with reductions in weight and BMI. A slight reduction of body fat, both with and without orlistat treatment, correlated with reduction in BMI after adjustment for baseline values. Blood pressure was unaltered by orlistat. Calorie intake was reduced with orlistat and the decrease noted in % fat and increase in % carbohydrate was significant only in those taking orlistat. The addition of exercise (Group 3 cf. Group 2) altered no parameter.
Conclusions: Orlistat improves endothelial function and reduces body weight, BMI, fasting total and LDL-cholesterol in obese adolescents when combined with dietary control. Improvement in endothelial function if maintained could reflect long term cardiovascular benefit.
SDF-1α Analogue (CTCE-0214) Can Enhance Survival and Migration of Human Mesenchymal Stem Cells Under Anoikis Stress
JL Yu,1 J Robles,1 YP Liu,1 J Nicholles,2 GCF Chan1
Departments of 1Paediatrics and Adolescent Medicine & 2Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
Background: Mesenchymal stem cells (MSCs) have been applied to a variety of clinical conditions. However, several barriers hinder their usage. MSCs are adherent cells and require prior detachment into suspension for delivery. This disruption of cell-extracellular matrix interaction is known as anoikis and will induce massive cell death. This study focused on the migratory and survival mechanisms of MSCs under anoikis stress and explored the potential method to minimise such adversity.
Materials and Methods: Human MSCs was obtained from normal human bone marrow transplantation donors with written informed consent under the approval of IRB of HKU-HKWC Hospitals. The ex-vivo expansion of human MSCs as we previously described (Li J, NJH, 2004). In vitro anoikis stress was generated by seeding cells to the ultra-low attachment plate coated with the covalently bound hydrogel layer. CellTiter-Glo luminescent cell viability assay was used to test the cells viability. Expression of CXCR-4 & cell cycle analysis was tested by flow cytometry. Protein expression was assessed by Western analysis. Migration potential was evaluated by transwell cell migration assay with polycarbonate membrane inserted. GvHD mouse model was used to verify our findings in-vivo.
Results: Under non-adherent culture, anoikis induced MSCs to ball-like cellular aggregates which have better migratory response to stromal cell derived factor-1a (SDF-1a) or its analogue (CTCE-0214). It was correlated with increased expression of CXCR4 (receptor of SDF-1a) and can be blocked by CXCR4 inhibitor (AMD3100), suggesting this migration was CXCR4-dependent. Although the viability of MSCs under anoikis stress was dramatically reduced, the aggregates could overcome such adversity via possible paracrine support. CTCE-0214, which has longer half-life than native SDF-1α in-vivo, could promote cellular survival under anoikis. Our study showed that CTCE-0214 increased the expression of Bcl-2 and modulated the cell survival through autophagy in a time-dependent manner. Such favorable effects were further verified by in-vivo study. The homing and engraftment effect could be suppressed by CXCR4 blocker, AMD3100.
Conclusion: Under aniokis, MSCs exerted distinct migratory and survival characteristics. Their migration was facilitated by forming aggregates with better migratory response to SDF-1α. Compared to SDF-1α, CTCE-0214 exhibited better biological effects. Our approach provides a new perspective to maximise the MSCs delivery and may facilitate the clinical applications of MSCs.
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