Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations.

Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.

Respiratory viruses and atypical bacteria triggering severe asthma exacerbation in children.

1. Respiratory viruses and atypical bacteria were detected in 51.0% of Hong Kong children with asthma exacerbations, which was significantly higher than the detection rate of 27.3% in children with chronic stable asthma. 2. Co-infections of two or more respiratory pathogens were more commonly found in children with asthma exacerbations (10.7%) than in patients with stable asthma (2.6%). 3. Human rhinovirus infection was a significant risk factor for asthma exacerbations. 4. There was no significant association between the severity of asthma exacerbations and respiratory viral or atypical bacterial infections. 5. Routine use of macrolide antibiotics in the treatment of childhood asthma exacerbations should be discouraged.

Distribution of melamine in rat foetuses and neonates.

Pharmacokinetics of melamine has not been studied in pregnancies despite of the many reports on the effect on renal damage in adult and neonates. In this study, Sprague-Dawley rats have been used as a model to study the single-dose effect of melamine administration in late pregnancy and in neonates within 24h. Melamine concentrations in maternal serum, breast milk, whole foetus, amniotic fluid, neonatal serum and neonatal kidney was measured by liquid chromatography coupled with mass spectrometry. Melamine was detected in all the samples, including foetal rats and amniotic fluid in utero. Melamine was able to pass through placenta and reach the foetus, and to accumulate in lactating mammary gland and neonatal kidney. Moreover, melamine was eliminated through the placenta of the foetus and the kidneys of the neonates, and later excreted into the amniotic fluid. The study characterised for the first time the distribution of melamine in foetuses and neonates, providing reference for toxicological study of melamine during pregnancy.

Higher exercise frequency associated with lower blood pressure in Hong Kong adolescents: a population-based study.

The aim of this study was to determine the association between blood pressure and the frequency of structured physical training activity in Chinese adolescents. A total of 9558 students aged 11-18 years underwent anthropometric and blood pressure measurements in a cross-sectional growth study. Structured physical training activity was assessed by two simple self-administered questions and parents were asked to complete a questionnaire providing demographic information. Ninety per cent of eligible students participated in the study, of which 94% provided data on physical training frequency for final analysis. Of the boys, 22.6% and of the girls, 14.5% were physically active with extracurricular school exercise at least twice a week. Over half of the students did not regularly exercise except during physical education classes at school. Blood pressure had a positive correlation with body mass index (BMI). Both systolic blood pressure and diastolic blood pressure were substantially decreased with increased training frequency (P<0.05). Logistic regression adjusting for age, family history of hypertension, BMI and sleep duration showed that exercising two or more times a week had a negative relation with hypertension (odds ratio: 0.63, 95%CI 0.47-0.85). In conclusion, structured physical training activity of two or more times a week has a beneficial effect on blood pressure in Hong Kong children aged 11-18 years.

Natural history and predictors for progression of mild childhood obstructive sleep apnoea.

AIMS: The natural history of mild childhood obstructive sleep apnoea (OSA) was examined and factors associated with disease progression were identified. METHODS: Subjects were recruited from an epidemiological study which examined the prevalence of OSA in Chinese children aged 6-13 years. The first 56 consecutive children identified with mild OSA (apnoea-hypopnoea index 1-5) were invited for a repeat assessment 2 years after the diagnosis. RESULTS: 45 children participated in the follow-up study, in 13 of whom (29%) the OSA was found to have worsened. Compared with those in whom OSA had not worsened, the worsened OSA group had a greater increase in waist circumference, a higher prevalence of large tonsils (occupying > or =50% of the airway) at both baseline and follow-up, and a higher prevalence of habitual snoring at both baseline and follow-up. The presence of large tonsils had a positive predictive value of 53% and a negative predictive value of 83% for worsening OSA over a 2-year period. Multivariate linear regression analysis showed that the change in obstructive apnoea-hypopnoea index was associated with age at baseline (beta (SE) = -0.92 (0.34), p = 0.009), gender (male = 1; female = 0) (beta (SE) = 4.69 (1.29), p<0.001), presence of large tonsils at baseline (beta (SE) = 4.36 (1.24), p = 0.001), change in waist circumference (beta (SE) = 0.30 (0.09), p = 0.002) and persistently large tonsils (beta (SE) = 5.69 (1.36), p<0.001) over the 2-year period. CONCLUSIONS: Mild OSA in the majority of children does not resolve spontaneously. Subjects with tonsillar hypertrophy, especially boys, should be closely monitored to allow early detection of worsening OSA. Weight control should be stressed in the management of childhood OSA.

Cardiac remodelling and dysfunction in children with obstructive sleep apnoea: a community based study.

BACKGROUND: Childhood obstructive sleep apnoea (OSA) is suggested to be associated with cardiac structural abnormalities and dysfunction but existing evidence is limited and the treatment effect on echocardiographic outcome remains controversial. OBJECTIVE: To examine the presence of subclinical cardiac abnormalities in childhood OSA and the effects of treatment on cardiac changes. METHODS: Polysomnography (PSG) and echocardiographic examinations were performed in 101 children aged between 6 and 13 years who were invited from a community based questionnaire survey. They were classified into a reference group (apnoea-hypopnoea index (AHI) <1, n = 35), mild OSA group (AHI 1-5, n = 39) and moderate to severe group (AHI >5, n = 27) based on the PSG results. Treatments, including adenotonsillectomy or nasal steroids, were offered to the mild and moderate to severe OSA groups. RESULTS: The moderate to severe OSA group had greater right ventricular (RV) systolic volume index (RVSVI), lower RV ejection fraction (RVEF) and higher RV myocardial performance index (RVMPI) than the reference group. They also had more significant left ventricular (LV) diastolic dysfunction and remodelling with larger interventricular septal thickness index (IVSI) and relative wall thickness than those with lower AHI values. The moderate to severe OSA group had an increased risk of abnormal LV geometry compared with the reference group (odds ratio 4.21 (95% CI 1.35 to 13.12)). Log transformed AHI was associated with RVSVI (p = 0.0002), RVEF (p = 0.0001) and RVMPI (p<0.0001), independent of the effect of obesity. Improvement in RVMPI, IVSI and E/e' were observed in those with a significant reduction in AHI (>50%) comparing 6 month with baseline data. CONCLUSIONS: OSA is an independent risk factor for subclinical RV and LV dysfunction, and improvement in AHI is associated with reversibility of these abnormalities.

Suppression and recovery of the hypothalamic function after high-dose corticosteroid treatment in preterm infants.

BACKGROUND: High-dose systemic dexamethasone is effective in facilitating extubation of ventilated infants with bronchopulmonary dysplasia. Although the suppression and recovery of pituitary-adrenal response had been assessed after corticosteroid treatment in very low birth weight infants, its effect on hypothalamic function has not been longitudinally monitored. AIMS: This study was designed to assess the longitudinal hypothalamic response before, during and 4 weeks after a 3-week dose-tapering course of systemic dexamethasone treatment. PATIENTS AND METHODS: Twenty very low birth weight infants had blood collected for corticotropin-releasing hormone, ACTH and cortisol measurements immediately before starting dexamethasone (week 0), after receiving the maximum dose of treatment (week 1), at the end of the 3-week course (week 3) and 4 weeks after stopping corticosteroids (week 7). RESULTS: All circulating hormone concentrations were significantly suppressed during the treatment period at week 1 and week 3 compared with pretreatment concentrations at week 0 (p < 0.001). The recovery of pituitary function started early soon after week 1, whereas that of hypothalamus and adrenal functions started after the end of the dexamethasone course. Plasma ACTH concentration at week 7 had returned to the pretreatment level, but plasma corticotropin-releasing hormone (p < 0.05) and serum cortisol (p < 0.001) concentrations remained significantly suppressed. Partial recovery of hypothalamic and adrenal function was observed at week 7 (62 vs. 36% of their pretreatment levels, respectively). CONCLUSION: Our findings suggest that the hypothalamic function is suppressed during systemic corticosteroid treatment but partial recovery occurs 4 weeks after stopping therapy. Even in preterm infants, the hypothalamic-pituitary-adrenal axis behaves in a similar manner as in adult subjects and the pituitary function recovers earlier than that of hypothalamus and adrenals.

Ambulatory blood pressure in children with obstructive sleep apnoea: a community based study.

BACKGROUND: Childhood obstructive sleep apnoea (OSA) is increasingly being recognised. Its effects on blood pressure (BP) elevation and hypertension are still controversial. OBJECTIVE: To evaluate the association between OSA and ambulatory BP in children. METHODS: Children aged 6-13 years from randomly selected schools were invited to undergo overnight sleep study and ambulatory BP monitoring after completing a validated OSA questionnaire. OSA was diagnosed if the obstructive apnoea-hypopnoea index (AHI) was >1, and normal controls had AHI <1 and snoring <3 nights per week. Children with OSA were subdivided into a mild group (AHI 1-5) and moderate to severe group (AHI >5). RESULTS: 306 subjects had valid sleep and daytime BP data. Children with OSA had significantly higher BP than normal healthy children during both sleep and wakefulness. BP levels increased with the severity of OSA, and children with moderate to severe disease (AHI >5) were at significantly higher risk for nocturnal systolic (OR 3.9 (95% CI 1.4 to 10.5)) and diastolic (OR 3.3 (95% CI 1.4 to 8.1)) hypertension. Multiple linear regression revealed a significant association between oxygen desaturation index and AHI with daytime and nocturnal BP, respectively, independent of obesity. CONCLUSIONS: OSA was associated with elevated daytime and nocturnal BP, and is an independent predictor of nocturnal hypertension. This has important clinical implications as childhood elevated BP predicts future cardiovascular risks. Future studies should examine the effect of therapy for OSA on changes in BP.

In vitro and clinical immunomodulatory effects of a novel Pentaherbs concoction for atopic dermatitis.

BACKGROUND: Our group recently reported a randomized and placebo-controlled clinical trial on the efficacy of a twice-daily concoction of five herbal ingredients (Pentaherbs formulation, PHF) in treating children with atopic dermatitis (AD). OBJECTIVES: To investigate the immunomodulatory effects that may be induced by PHF treatment. METHODS: We investigated the effects of PHF on cytotoxicity and proliferation of phytohaemagglutinin (PHA)- and staphylococcal enterotoxin B (SEB)-stimulated peripheral blood mononuclear cells (PBMC) isolated from buffy coat of blood donors. PHF-induced immunomodulation for five inflammatory mediators in cultured PBMC was measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. The effects of a 3-month, open-label study of PHF on circulating inflammatory mediators in children with AD were also assessed. RESULTS: PHF at up to 1 mg mL(-1) dose-dependently suppressed PBMC proliferation. The addition of PHF to cultured PBMC reduced supernatant concentrations of brain-derived neurotrophic factor (BDNF), interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in response to PHA, and BDNF and thymus and activation-regulated chemokine (TARC) following SEB stimulation. PHF increased epithelial cell-derived neutrophil activating peptide-78 levels in culture supernatants. At the RNA level, PHF suppressed the transcription of BDNF, TARC, IFN-gamma and TNF-alpha. Twenty-eight children with AD were treated with PHF for 3 months, and their mean plasma concentrations of BDNF and TARC decreased significantly from 1798 pg mL(-1) and 824 pg mL(-1) at baseline to 1378 pg mL(-1) and 492 pg mL(-1) (P = 0.002 and 0.013, respectively) upon study completion. CONCLUSIONS: PHF possesses in vitro and in vivo immunomodulatory properties that may mediate the clinical efficacy observed in AD treatment.

Efficacy and tolerability of a Chinese herbal medicine concoction for treatment of atopic dermatitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: There has been considerable interest in traditional Chinese herbal medicine (TCHM) as a treatment for atopic dermatitis (AD). A twice-daily concoction of an ancestral formula containing five herbs has been found to be beneficial in an open study. OBJECTIVES: To assess the efficacy and tolerability of the concoction in children with AD. METHODS: Following a 2-week run-in period, children with long-standing moderate-to-severe AD were randomized to receive a 12-week treatment with twice-daily dosing of three capsules of either TCHM or placebo. The SCORing of Atopic Dermatitis (SCORAD) score, Children's Dermatology Life Quality Index (CDLQI), allergic rhinitis score, and requirement for topical corticosteroid and oral antihistamine were assessed before and at weeks 4, 8, 12 and 16 after treatment. Adverse events, tolerability, haematological and biochemical parameters were monitored during the study. RESULTS: Eighty-five children with AD were recruited. Over 12 weeks, the mean SCORAD score fell from 58.3 to 49.7 in the TCHM group (n = 42; P = 0.003) and from 56.9 to 46.9 in the placebo group (n = 43; P = 0.001). However, there was no significant difference in the scores at the corresponding time points between the two groups. The CDLQI in TCHM-treated patients was significantly improved compared with patients receiving placebo at the end of the 3-month treatment and 4 weeks after stopping therapy (P = 0.008 and 0.059, respectively). The total amount of topical corticosteroid used was also significantly reduced by one-third in the TCHM group (P = 0.024). No serious adverse effects were observed between the groups. CONCLUSIONS: The TCHM concoction is efficacious in improving quality of life and reducing topical corticosteroid use in children with moderate-to-severe AD. The formulation was palatable and well tolerated.

Which aeroallergens are associated with eczema severity?

We investigated if a correlation exists between aeroallergen sensitization and the severity of eczema. Data on aeroallergen response to skin-prick testing (SPT) and disease severity of children with eczema (n = 119) were evaluated. Atopy, as defined by at least one positive response to aeroallergen skin prick testing, was found in > 90% of eczema patients. House dust mite was the most commonly sensitized aeroallergen, followed by cat fur. Dermatophagoides pteronyssinus and Dermatophagoides farinae sensitization were associated with eczema severity (present in 67% of the mild and 97% of the severe group; P = 0.001). However, there was no association between eczema severity and higher strengths of SPT response (defined as SPT > 1+ to dust mites or dust). Atopy to moulds, Bermuda grass, cockroach, cat and dog was less prevalent and was not associated with eczema severity. It is sensible to advise parents on specific avoidance strategies only in severely affected children who have a definitive history of eczema exacerbation by specific aeroallergens and who are not responsive to conventional treatment.

Waist circumference and body mass index in Chinese children: cutoff values for predicting cardiovascular risk factors.

BACKGROUND: Body mass index (BMI) and waist circumference (WC) correlate with cardiovascular (CV) risk factors in childhood which track into adulthood. WC provides a measure of central obesity, which has been specifically associated with CV risk factors. Reference standards for WC, and for WC and BMI risk threshold values are not established in Chinese children. OBJECTIVES: To construct reference percentile charts of WC, establish relationships between WC, BMI and other risk factors, and propose WC and BMI threshold values predictive of CV risk factors in Hong Kong ethnic Chinese children. METHODS: Weight, height, waist and hip circumference were measured in 2593 (52% boys, 47% girls) randomly sampled Hong Kong school children aged 6-12 years. In 958 of these and 97 additional overweight children (n=1055), the relationships between WC, BMI, waist/hip and waist/height ratio and six age-adjusted CV risk factors (>85% percentile levels of blood pressure (BP), fasting triglycerides, low-density lipoprotein (LDL) cholesterol, glucose and insulin levels, and <15% percentile levels of high-density lipoprotein (HDL) cholesterol) were studied. Receiver-operating characteristic analysis was employed to derive optimal age-adjusted sex-specific WC and BMI thresholds for predicting these measures of risk. RESULTS: WC percentiles were constructed. WC correlated slightly more than BMI with CV risk factors and most strongly with insulin and systolic BP, but poorly or not with LDL and glucose. Optimal WC and BMI risk thresholds for predicting four of these six CV risk factors were ca. the 85th percentiles (sensitivities approximately 0.8, specificities approximately 0.87) with age-specific cutoff values in girls/boys from approximately 57/58 to approximately 71/76 cm and 17/18 to 22/23 kg/m(2). CONCLUSION: These are the first set of WC reference data for Chinese children. WC risk cutoff values are proposed which, despite a smaller waist in Chinese children, are similar to those reported for American children. WC percentiles may reflect population risk.

Induced sputum inflammatory measures correlate with disease severity in children with obstructive sleep apnoea.

OBJECTIVE: To establish the association between airway inflammation and severity of obstructive sleep apnoea (OSA) in children. METHODS: Consecutive children presenting with symptoms suggestive of OSA were recruited. They completed a sleep apnoea symptom questionnaire, underwent physical examination, spirometry, sputum induction and an overnight polysomnography. Adequate sputum contained <50% squamous epithelial cells, and OSA was diagnosed if the obstructive apnoea index was >1. RESULTS: 73 children with a median (interquartile range (IQR)) age of 11.3 (10.0-13.2) years were recruited. There were 21 girls and the median body mass index of the group was 24.0 (18.0-27.0) kg/m2. The most common presenting symptoms were habitual snoring, mouth breathing and prone sleeping position. Sputum induction was successful in 43 (59%) children, of whom 14 were found to have OSA. Children with OSA had significantly greater percentage sputum neutrophil than those without OSA (18.5 (IQR 8.0-42.0) v 4 (IQR 3.0-11.3), p = 0.006). On multiple regression analysis, percentage sputum neutrophil was significantly associated with OSA (odds ratio = 1.1, p = 0.013). CONCLUSION: Children with OSA had airway inflammation characterised by a marked increase in neutrophils. Further studies are needed to confirm these findings and to better define the downstream cellular interactions and molecular pathogenesis in childhood OSA.

Exhaled nitric oxide levels are not correlated with eczema severity in Chinese children with atopic dermatitis.

Asthma is a common atopic disease associated with atopic dermatitis (AD) and allergic rhinitis (AR). Exhaled nitric oxide level (eNO) has been found to be an interesting noninvasive marker of disease severity in children with asthma. However, it is uncertain if eNO may be confounded by any coexisting AD or AR. In this study, eNO in Chinese children with moderate-to-severe AD and no asthma symptoms (n = 53) was measured online by a chemiluminescence analyzer. Severity of AD was assessed using the objective SCORing-Atopic-Dermatitis score and coexisting allergic rhinitis with the Allergic-Rhinitis-Score (ARS). Patients with active symptoms of asthma or inhaled/intranasal corticosteroids were excluded. There was no difference in eNO between genders and no correlation between eNO and AD severity regardless of ARS or bronchial reactivity status. ENO appears to be a noninvasive marker whose level is independent of the two atopic diseases of AD and AR in children old enough to perform exhalation maneuver.

Lesson from performing SCORADs in children with atopic dermatitis: subjective symptoms do not correlate well with disease extent or intensity.

BACKGROUND: Atopic dermatitis (AD) is a distressing disease associated with pruritus and sleep disturbance. It is not known how well these symptoms correlate with the extent and intensity of eczematous involvement. We evaluated whether: (i) the level of sleep loss correlates with pruritus and (ii) the level of pruritus correlates with the extent or severity of AD in children according to the SCORing Atopic Dermatitis (SCORAD) index. METHOD: Patients with AD younger than 18 years old were recruited from the pediatric dermatology clinic of a university teaching hospital, and AD severity was evaluated by the SCORAD index. RESULTS: One hundred and eighty-two Chinese children with AD (107 boys and 75 girls) [mean (SD) age of 9.6 (4.2) years] were recruited. Their mean (SD) overall SCORAD was 30.1 (19.2). Sleep loss was strongly correlated with pruritus (r = 0.57, P < 0.001). However, the two subjective symptoms were only weakly correlated with the objective signs (extent and intensity) of AD. The correlations between pruritus and extent and intensity were 0.42 (P < 0.001) and 0.38 (P < 0.001), respectively, and the correlations between sleep loss and extent and intensity were 0.38 (P < 0.001) and 0.34 (P < 0.001), respectively. CONCLUSION: We speculate that the lack of a better correlation was either because pruritus and sleep loss as reported by parents were imprecise, or that mechanisms other than disease extent or severity are responsible for the pathogenesis of these subjective symptoms.