Guidance on the management of familial hypercholesterolaemia in Hong Kong: an expert panel consensus viewpoin.

In 2016, meetings of groups of physicians and paediatricians with a special interest in lipid disorders and familial hypercholesterolaemia were held to discuss several domains of management of familial hypercholesterolaemia in adults and children in Hong Kong. After reviewing the evidence and guidelines for the diagnosis, screening, and management of familial hypercholesterolaemia, consensus was reached on the following aspects: clinical features, diagnostic criteria, screening in adults, screening in children, management in relation to target plasma low-density lipoprotein cholesterol levels, detection of atherosclerosis, lifestyle and behaviour modification, and pharmacotherapy.

Screening for dysglycaemia by oral glucose tolerance test should be recommended in all women with polycystic ovary syndrome.

STUDY QUESTION: Should fasting glucose (FG) or an oral glucose tolerance test (OGTT) be used to screen for dysglycaemia in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: A full OGTT should be recommended as the screening method for dysglycaemia in women with PCOS, regardless of BMI or family history of diabetes mellitus (DM). STUDY DESIGN, SIZE, DURATION: A cross-sectional study on 467 Chinese women diagnosed with PCOS by the Rotterdam criteria between January 2010 to December 2013. PARTICIPANTS, SETTING, METHODS: The study was done at a university hospital in Hong Kong. All subjects underwent a 75 g OGTT after overnight fasting. We evaluated the performance of FG alone, when compared with the full OGTT, in identifying subjects with dysglycaemia (prediabetes or DM, according to the 2010 diagnostic criteria of the American Diabetes Association). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 467 subjects, 58 (12.4%) had dysglycaemia, among which 46 (9.8%) had prediabetes and 12 (2.6%) had DM, including 4 with known DM. Of the 46 subjects with prediabetes, 25 (54.3%) had normal FG and of the 8 subjects with screened DM in this study, 1 (12.5%) had normal FG. The sensitivity of FG alone in screening for prediabetes, DM and overall dysglycaemia were 45.7, 87.5 and 48.1%, respectively, i.e. missing 54.3% of prediabetes and 12.5% of DM cases as defined by the OGTT. Among the 54 subjects with screened dysglycaemia, 20 (37.0%) had BMI < 25 kg/m(2) and 35 (64.8%) had no family history of DM. LIMITATIONS, REASONS FOR CAUTION: We only reported on the biochemical diagnosis of DM based on a single time point. In clinical practice, confirmatory results at another time point is required for definitive diagnosis in asymptomatic subjects. WIDER IMPLICATIONS OF THE FINDINGS: There is an ongoing debate as to whether FG or an OGTT should be used as a screening method for dysglycaemia in women with PCOS. Some guidelines also recommend glucose screening only in those who are overweight and/or having family history of diabetes (DM). There have been scarce data on this issue in the Chinese population, which the current study aims at addressing. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a research grant from the Hong Kong Obstetrical and Gynaecological Trust Fund, as well as internal research funding of the Department of Obstetrics and Gynaecology, The University of Hong Kong. All authors have no competing interests.

Mild hypoxic-ischemic injury in the neonatal rat brain: longitudinal evaluation of white matter using diffusion tensor MR imaging.

BACKGROUND AND PURPOSE: Selective white matter (WM) damage is a known sequela of mild hypoxic-ischemic (HI) injury in the neonatal rat model. The aim of this study was to evaluate longitudinally mild HI-induced WM damage (represented by the external capsule [EC]) by diffusion tensor MR imaging (DTI) and to correlate the findings with histology. MATERIALS AND METHODS: Seven-day-old Sprague-Dawley rats (n = 19) underwent unilateral ligation of the left common carotid artery followed by hypoxia for 50 minutes to create mild HI injury. DTI was performed longitudinally at 5 time points from day 1 to day 90 postinjury (n = 19, 16, 13, 11, 9, respectively), and fractional anisotropy (FA), trace, radial diffusivity (lambda( perpendicular)), and axial diffusivity (lambda(//)) of the injury and control contralateral ECs were quantified. Rats were randomly sacrificed (n = 15, in total), and the corresponding ECs were stained with hematoxylin-eosin, Luxol fast blue (LFB), and neurofilament (NF) to evaluate morphologic changes, amount of myelin, and axonal count at every time point. A paired t test was applied to evaluate statistical differences between both ECs, and the Pearson correlation test was used to evaluate the relationships between DTI indices and histologic evaluations. In addition, longitudinal changes in DTI indices and histologic evaluations were analyzed by a linear mixed model and an analysis of variance test, respectively. RESULTS: We demonstrated significantly decreased FA, increased lambda( perpendicular), and similar lambda(//) in the injury compared with the control EC, which was persistent through all time points. Histologic evaluation by LFB and NF staining showed reduced myelin stain intensity in the injury EC and similar axonal counts in both ECs. Longitudinally, there was an increase in FA, a decrease in lambda( perpendicular) and trace, and stability in lambda(//) in both ECs. Also, there was progressive reduction in the differences in FA, trace, and lambda( perpendicular) between the injury and control EC, especially between day 1 and day 7 postinjury and in tandem with changes in myelin stain. FA was significantly correlated with myelin stain (r = 0.681, P < .01) and axonal count (r = 0.673, P < .01), whereas lambda( perpendicular) was significantly correlated with myelin stain only (r = -0.528, P < .01), and lambda(//), with axonal count only (r = 0.372, P = .043). CONCLUSIONS: Diffusion indices can reflect dysmyelination in mild HI injury, continual myelination of both injury and control ECs with growth, and the partial recovery of myelin postinjury. We propose that diffusion indices may be used as biomarkers to monitor noninvasively the longitudinal changes of mild HI-induced WM damage.

Drug carrier systems based on collagen-alginate composite structures for improving the performance of GDNF-secreting HEK293 cells.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor. Development of drug delivery technologies facilitating controlled release of GDNF is critical to applying GDNF in treating neurodegenerative diseases. We previously developed 3D collagen microspheres and demonstrated enhanced GDNF secretion after encapsulation of HEK293 cells, which were transduced to overexpress GDNF in these microspheres. However, the entrapped HEK293 cells were able to migrate out of the collagen microspheres, making it undesirable for clinical applications. In this report, we investigate two new carrier designs, namely collagen-alginate composite gel and collagen microspheres embedded in alginate gel in preventing cell leakage, maintaining cell growth and controlling GDNF secretion in the HEK293 cells. We demonstrated that inclusion of alginate gel in both designs is efficient in preventing cell leakage to the surrounding yet permitting the GDNF secretion, although the cellular growth rate is reduced in an alginate concentration dependent manner. Differential patterns of GDNF secretion in the two designs were demonstrated. The collagen-alginate composite gel maintains a more or less constant GDNF secretion over time while the collagen microspheres embedded in alginate gel continue to increase the secretion level of GDNF over time. This study contributes towards the development of cell-based GDNF delivery devices for the future therapeutics of neurodegenerative diseases.

A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene.

Osteoporosis pseudoglioma syndrome (OPPG) is an autosomal recessive disorder due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we report two novel missense mutations found in a southern Chinese family of a non-consanguineous marriage. Three out of four children had blindness, low bone mineral density (BMD) and multiple fractures in their childhood. Genotyping by DNA sequencing demonstrated 2 new mutations in exon 7 of the LRP5 gene. Tryptophans at amino acid residue positions 478 and 504 were replaced by arginine (W478R) and cysteine (W504C), respectively. While the parents that possessed either heterozygous W478R or W504C were apparently normal, all affected subjects were compound heterozygotes for the W478R and W504C mutations in the LRP5 gene. W478R is located immediately C-terminal to the third YWTD repeat of the second YWTD/EGF domain in LRP5, while W504C is located between the third and the fourth YWTD repeats of the second YWTD/EGF domain in LRP5. Using LRP5-related proteins, such as the low-density lipoprotein receptor (LDLR) and nidogen as reference models, a homology model of LRP5 suggested that the observed mutations may affect the molecular interactions of LRP5 and so lead to the observed OPPG phenotypes.

Hypoxic-ischemic brain injury in the neonatal rat model: relationship between lesion size at early MR imaging and irreversible infarction.

BACKGROUND AND PURPOSE: By using a neonatal rat hypoxia-ischemia (HI) model, we studied the relationship between lesion volume-measured by diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) at an early time point-and irreversible infarct volume. We also evaluated the optimal apparent diffusion coefficient (ADC) threshold that provides the best correlation with irreversible infarct size. MATERIALS AND METHODS: Twenty-three neonatal rats underwent right common carotid artery ligation and hypoxia. MR imaging was performed 1-2 hours post-HI by using DWI and T2WI and at day 4 post-HI by using T2WI. Lesion volumes relative to whole brain (%LV) were measured on ADC maps by using different relative ADC thresholds 60%-80% of mean contralateral ADC and T2WI. Pearson correlation and multiple linear regression analysis were used to study the relationships between ln(%LV) at MR imaging and %LV at histopathology. RESULTS: At 1-2 hours post-HI, all lesion volume measurements on DWI were significantly correlated with the infarct volume on histopathology, with the best correlation attained at the 80% ADC threshold (r = 0.738; P < .001). The estimated regression formula was %LV on histopathology = 20.60 + 3.33 ln(%LV on 80% ADC threshold) (adjusted R(2) = 0.523; P < .001). Lesion volume at 1-2 hours post-HI tended to underestimate the final infarct volume. CONCLUSION: Early post-HI MR imaging by using DWI correlates moderately well with the size of irreversible infarct, especially when measured by using a relative ADC threshold of 80% mean contralateral ADC.

Clinical and electrophysiological features in Chinese patients with Kennedy's disease.

Kennedy's disease is a X-linked neuromuscular disorder caused by an expanded trinucleotide repeat in the androgen receptor gene. To ascertain the clinical diagnosis of Kennedy's disease in a Chinese population, we used a rapid, accurate PCR-based sizing method for the CAG repeat allelotype. The clinical and electrophysiological features of affected patients are described. The CAG repeats ranged from 43 to 53 and were inversely correlated with the age of onset (r = -0.63; P < 0.005).

Phaeochromocytoma in children.

Phaeochromocytoma is a rare disease in childhood with a subtle and wide range of clinical presentations. We report two confirmed cases and one potential case of phaeochromocytoma, each belonging to a different disease spectrum or syndromal disorder, namely sporadic phaeochromocytoma, von Hippel-Lindau disease, and multiple endocrine neoplasia type 2a. Knowledge of the molecular basis of the condition helps to make the diagnosis. Affected individuals and their family members should be screened for any associated syndromal disorders that can carry a substantial degree of morbidity and mortality.

A novel FUCA1 mutation causing fucosidosis in a Chinese boy.

We report a 6-year-old boy with an intermediate form of fucosidosis.

Perinatal hypoxia-/ischemia-induced endothelin-1 mRNA in astrocyte-like and endothelial cells.

Under pathological conditions in the adult CNS, such as ischemia, subarachnoid hemorrhage and Alzheimer's disease, endothelin (ET)-1- and -3-like immunoreactivities are elevated in astrocytes of the injured adult brain. However, it is not clear whether this is due to increased synthesis or increased binding of ET-1. Further, it is not known whether ET-1 expression is altered in the perinatal brain after cerebral hypoxia/ischemia (H/I). Here, we determined the sites of ET-1 expression in perinatal mouse brain after H/I injury by in situ hybridization using a probe specific for the ET-1 gene. Astrocyte-like cells, which do not normally express ET-1 mRNA, showed high levels of ET-1 mRNA expression. Endothelial cells of the capillaries and small vessels also showed an increased level of ET-1 mRNA. Our data suggest that ET-1 mRNA levels in the astrocyte-like cells and vascular endothelial cells are dynamically regulated by ischemia and may participate in perinatal ischemia-related neural damage.

Insulin-like growth factor 1 promotes cord blood T cell maturation and inhibits its spontaneous and phytohemagglutinin-induced apoptosis through different mechanisms.

Functional immaturity of neonatal T cells is related to their immature phenotype, with the majority of neonatal T cells of naive (CD45RA+) T cells. The progression of T cells from naive cells to effector cells is dependent on the survival of Ag-specific T cells and their resistance to apoptosis. In this study, we showed for the first time that insulin-like growth factor 1 (IGF-1) converted cord blood CD45RA+ T cells to CD45RO+ T cells and inhibited cord blood T cell apoptosis. We found cord blood T cells stimulated with PHA would result in gradual loss of CD45RA and gain of CD45RO expression. IGF-1 further increased the loss of CD45RA and enhanced CD45RO expression in PHA-stimulated cord blood T cells. In addition, IGF-1 prevented cord blood T cells from spontaneous apoptosis through a mechanism other than Fas/FasL. In PHA-activated cord blood T cells, IGF-1 prevented both naive (CD45RA+) and memory/mature (CD45RO+) T cells from apoptosis. Moreover, cord blood T cells cultured with IGF-1 and PHA had a higher resistance to anti-Fas-induced apoptosis as compared with PHA-activated cord blood T cells. IGF-1 also significantly inhibited PHA-induced Fas expression on cord blood T cells. These results demonstrate that IGF-1 promotes the maturation and maintains the survival of cord blood T cells. Its antiapoptotic effect in PHA-activated cord blood T cells may be mediated through the down-regulation of Fas expression.

The effect of 3 years of recombinant growth hormone therapy on glucose metabolism in short Chinese children with beta-thalassemia major.

Growth retardation and diabetes mellitus are common in children and adolescents with beta-thalassemia major despite hypertransfusion regimen and iron chelation therapy. The purpose of this study was to investigate the effects of growth hormone (GH) treatment on glucose metabolism in children with beta-thalassemia major. GH therapy for 3 years improved the height SD scores of eight short prepubertal Chinese children with beta-thalassemia major from -2.15 +/- 0.90 to -1.14 +/- 0.78 (paired t-test, p = 0.01) without excessive advancement in bone age (ABA/CA = 0.95 +/- 0.27). There was no deleterious effect on glucose metabolism with no change in fasting blood sugar, serum fructosamine, fasting and stimulated insulin to intravenous glucose infusion (sum of 1+3 min insulin, In 1+3'; incremental insulin 0-10 min area above fasting concentrations, deltaInAUC0-10'; ratio of incremental 0-10 min insulin area above fasting concentrations over glucose area above fasting concentrations, delta0-10'AUCIn/G; ratio of incremental 0-10 min insulin over peak glucose above basal 0-10 min, delta0-10'InAUC/deltaGPeak), and glucose disappearance coefficient (Kg). Short term GH therapy improves the height of children with beta-thalassemia major but the effect of treatment on final height still needs to be determined.

Epidemiology of diabetes mellitus in children in Hong Kong: the Hong Kong childhood diabetes register.

OBJECTIVES: To establish a registry for Chinese children with onset of type 1 (insulin dependent) diabetes mellitus before 15 years of age and to determine the incidence of childhood onset type 1 diabetes mellitus in Chinese children in Hong Kong. RESEARCH DESIGN AND METHODS: A registry was established in 1997 to collect childhood diabetes cases retrospectively from all districts in Hong Kong. The study included all newly diagnosed cases of diabetes with onset < 15 yr of age from 1st January 1984 to 31 December 1996. Primary ascertainment was based on review of medical records at all regional public hospitals in Hong Kong and survey of all the registered practitioners in Hong Kong. The secondary source of validation was made impractical, if not impossible, because of the recent implementation of the Personal Data Privacy Ordinance in Hong Kong. RESULTS: A total of 255 diabetic cases were identified, 227 type 1 diabetes mellitus (218 were Chinese), 18 type 2 diabetes mellitus and 11 secondary diabetes. 246 patients were Chinese and 9 non-Chinese. The age-standardized incidence of type 1 and type 2 diabetes mellitus in southern Chinese children in Hong Kong was 1.4/100,000/yr and 0.1/100,000/yr respectively for children < 15 yr of age during the study period. The incidence rates for type 1 diabetes were 0.9, 1.5 and 1.7 per 100,000/yr for 0-4 years, 5 to 9 years and 10 to 14 years age-groups respectively. The incidence for males was 1.2/100,000/yr and for females 1.7/100,000/yr. A significant increase in the incidence was demonstrated during the study period by simple linear regression (slope 0.14/100,000/year, r2 = 0.73, p = 0.0002) CONCLUSIONS: A diabetic registry is established in Hong Kong. This study documents a very low incidence rate of childhood type 1 diabetes mellitus in southern Chinese children in Hong Kong and we have seen an increasing incidence of the disease in the past 13 years.

IGF-I increases interferon-gamma and IL-6 mRNA expression and protein production in neonatal mononuclear cells.

Neonates are vulnerable to infections because of their immature immunity. IGF-I has been reported to have profound positive effects on immune function. In this study, we investigated the effects of IGF-I on neonatal immunity. The production of IL-2, IL-4, and interferon-gamma in phytohemagglutinin (PHA)-stimulated neonatal mononuclear cells (MNC) was significantly decreased when compared with that of adults. IGF-I alone induced a high level of IL-6 mRNA expression and protein production in neonatal MNC. IGF-I significantly increased mRNA expression and protein production of both IL-6 and interferon-y but had no influence on that of IL-2 and IL-4 in PHA-stimulated neonatal MNC. Moreover, it increased neonatal interferon-gamma production in PHA-stimulated MNC to a level similar to that of adults. IGF-I could further enhance the mRNA expression of lymphocyte-activation gene 3, which is associated with interferon-gamma production and differentiation of T-helper 1 lymphocytes, in PHA-stimulated neonatal MNC. These results suggest IGF-I could promote maturation of neonatal T cells, and its potential use to enhance neonatal immunity deserves further study.

Effect of insulin-like growth factor 1 on PHA-stimulated cord blood mononuclear cell telomerase activity.

Telomerase may contribute to the capacity for cell replication by compensating for the loss of telomere length. Exploring the use of biological modifiers in increasing cellular replicative potential through telomerase activity may be useful for in vitro expansion of haemopoietic stem cells for transplantation or lymphoid cells for adoptive immunotherapy. In this study we showed for the first time that insulin-like growth factor 1 (IGF-1) modulated telomerase activity in human cord blood mononuclear cells (MNC) and some of the known functional determinants of telomerase activity. We found that cord blood MNC expressed constitutively a low level of telomerase activity and human telomerase reverse transcriptase (hTRT) mRNA, and a high level of human telomerase RNA component (hTR) and telomerase-associated protein-1 (TP1) mRNA. Interestingly, IGF-I alone did not increase the telomerase activity of cord blood MNC but could enhance the PHA-induced increase in telomerase activity. These alterations in telomerase activity were not completely in phase with those of proliferation response. On the other hand, IGF-I did not alter hTRT mRNA expression but enhanced the PHA-induced increase in hTRT whereas TP1 mRNA expression was stimulated by either IGF-I or PHA but showed no additive increase when stimulated by both IGF-1 and PHA. Neither IGF-1 nor PHA altered hTR expression. Finally, the temporal dynamics of hTRT mRNA expression and telomerase activity in cord blood MNC over 5 d in culture were not totally concordant. suggesting that key factors other than hTRT were involved in regulating telomerase activity in cord blood MNC. The modulatory effect of IGF-1 on telomerase activity supports its potential role in increasing replicative potential of cord blood lymphoid cells or haemopoietic stem cells.

Serum growth hormone (GH) binding protein, IGF-I and IGFBP-3 in patients with beta-thalassaemia major and the effect of GH treatment.

OBJECTIVE: Levels of IGFI have been shown to be low in transfusion-dependent thalassaemia and there is preliminary evidence to suggest that this may be reversed by GH treatment. In this further study we have evaluated serum growth hormone (GH) binding protein (GHBP), IGF-I and IGFBP-3 in patients with beta-thalassaemia major and the effects of GH treatment on these various parameters. PATIENTS: Fifty-six transfusion dependent patients with beta-thalassaemia major without GH deficiency between 2 and 20 years of age were studied. Thirteen non-GH deficient patients with heights of -1.5 SD or more were treated with GH at a dose of 0.14 IU/kg/day subcutaneously for 1 year. MEASUREMENTS: Serum GHBP, IGF-I and IGFBP-3 were measured in all the patients. In the 13 patients treated with GH, these serum parameters were measured before and after 3, 6 and 12 months of treatment. RESULTS: The mean serum GHBP concentrations were normal in both prepubertal and pubertal children but the serum IGF-I and IGFBP-3 concentrations were low throughout childhood and adolescence. There was a significant correlation between serum IGF-I and IGFBP-3 concentrations (r = 0.79; P = 0.0001) but there was no correlation between the height SDS of the patients with serum GHBP, IGF-I or IGFBP-3 levels. GH treatment in the 13 patients resulted in significant growth acceleration associated with a significant rise in the serum IGF-I and IGFBP-3 and a significant fall in serum GHBP concentrations. CONCLUSIONS: The low serum concentrations of IGF-I and IGFBP-3 in the presence of normal GH reserve and serum GHBP concentrations in patients with beta-thalassaemia suggest a state of partial GH insensitivity at the post-receptor level. This partial GH insensitivity state can be overcome by supraphysiological doses of exogenous GH. The lack of correlation of IGF-I, IGFBP-3 and GHBP with height SDS of the patients imply that the growth failure commonly observed in patients with beta-thalassaemia major may not be specifically related to dysregulation of the GH-IGF-I axis. GH therapy resulted in significant increase in serum IGF-I and IGFBP-3 but a significant fall in GHBP.

Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus.

BACKGROUND: Human infection with an avian influenza A virus (subtype H5N1) was reported recently in Hong Kong. We describe the clinical presentation of the first 12 patients and options for rapid viral diagnosis. METHODS: Case notes of 12 patients with virus-culture-confirmed influenza A H5N1 infection were analysed. The clinical presentation and risk factors associated with severe disease were defined and the results of methods for rapid virus diagnosis were compared. FINDINGS: Patients ranged from 1 to 60 years of age. Clinical presentation was that of an influenza-like illness with evidence of pneumonia in seven patients. All seven patients older than 13 years had severe disease (four deaths), whereas children 5 years or younger had mild symptoms with the exception of one who died with Reye's syndrome associated with intake of aspirin. Gastrointestinal manifestations, raised liver enzymes, renal failure unrelated to rhabdomyolysis, and pancytopenia were unusually prominent. Factors associated with severe disease included older age, delay in hospitalisation, lower-respiratory-tract involvement, and a low total peripheral white blood cell count or lymphopenia at admission. An H5-specific reverse-transcription PCR assay (RT-PCR) was useful for rapid detection of virus directly in respiratory specimens. A commercially available enzyme immunoassay was more sensitive than direct immunofluorescence for rapid viral diagnosis. Direct immunofluorescence with an H5-specific monoclonal antibody pool was useful for rapid exclusion of H5-subtype infection. INTERPRETATION: Avian Influenza A H5N1 virus causes human influenza-like illness with a high rate of complications in adults admitted to hospital. Rapid H5-subtype-specific laboratory diagnosis can be made by RT-PCR applied directly to clinical specimens.