A clinical prediction score using age at diagnosis and saline infusion test parameters can predict aldosterone-producing adenoma from idiopathic adrenal hyperplasia.

PURPOSE: Accurate subtyping of the primary aldosteronism into aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH) is important to direct for specific treatment modalities. The objective of the study was to compare the clinical and biochemical parameters of APA and IAH patients to derive a Clinical Prediction Score reliably predicting APA from IAH. METHODS: This was a retrospective multi-centre study recruiting 38 APA patients and 42 IAH patients from four major hospitals in Hong Kong using database from Surgical Outcomes Monitoring and Improvement Programme and Clinical Data Analysis and Reporting System. Their clinical and biochemical parameters were evaluated. RESULTS: Patients in APA group were younger than IAH group (mean age 48.6 ± 9.2 vs. 57.1 ± 7.3 years old, p < 0.001), had more suppressed renin before saline infusion in saline infusion test (SIT) (median 0.19 [IQR 0.15-0.37] vs. 0.39 [IQR 0.19-0.69] ng/mL/h, p = 0.01), and higher aldosterone level after saline infusion in SIT (median 674 [IQR 498-1000] vs. 327 [IQR 242-483] pmol/L, p < 0.001). A clinical prediction score using three parameters was devised, comprising age at diagnosis < 50 years, PRA before saline infusion in SIT ≤ 0.26 ng/mL/h, and aldosterone level after saline infusion in SIT ≥ 424 pmol/L. A score of 2 would predict APA with a sensitivity of 84.2% and specificity of 88.1%, and a score of 3 would predict APA with a sensitivity of 31.6% and specificity of 100%. CONCLUSIONS: Clinical Prediction Score based on the combination of age at diagnosis, PRA, and aldosterone level in the saline infusion tests could reliably predict APA from IAH.

Migrant status and childhood hospitalizations for asthma and other wheezing disorders.

BACKGROUND: In developed Western settings, asthma is more prevalent among second-generation compared to first-generation migrants. However, these studies are difficult to interpret as they include migrants of various ethnicities and countries of origin. OBJECTIVE: We assessed the association of parental migrant status with wheezing disorders among children born in Hong Kong, a developed non-Western setting, where many children have migrant parents from mainland China of the same ethnicity. METHODS: We used Cox regression to examine the adjusted associations of parental migrant status with time to first public hospital admission for asthma, bronchitis and bronchiolitis (International Classification of Diseases, Ninth Version Clinical Modification 466, 490 and 493) from 9 days to 12 years in a population-representative birth cohort of 8327 Chinese children in Hong Kong. RESULTS: Having both parents as migrants was associated with higher risk of hospitalization for asthma and other wheezing disorders, compared to both parents being Hong Kong born (hazard ratio 1.30, 95% confidence interval 1.05-1.60 from 9 days to 6 years), adjusted for type of hospital at birth, parental history of allergies, mother's age at birth, father's age at birth and highest parental education. CONCLUSIONS AND CLINICAL RELEVANCE: In the unique, non-Western context of Hong Kong, second-generation migrants had higher risk of hospitalization for childhood wheezing disorders compared to the native population, particularly before 6 years of age. Further study is required to clarify the underlying mechanisms involved.

Mode of delivery and childhood hospitalizations for asthma and other wheezing disorders.

BACKGROUND: Observationally, delivery by Caesarean section is associated with higher risk of childhood asthma and wheeze in developed Western settings, but associations are less consistent in other settings. OBJECTIVE: To examine the association of mode of delivery with hospitalizations for asthma and other wheezing disorders in a developed non-Western setting with high rates of Caesarean section. METHODS: Using Cox regression, we examined the adjusted association of mode of delivery with public hospital admissions for asthma, bronchitis, and bronchiolitis (International Classification of Diseases, Ninth Version Clinical Modification 466, 490 and 493) from 9 days to 12 years of age in a population-representative prospective birth cohort of 8327 Chinese children in Hong Kong. Confounders included sex, birth and parental characteristics, and socio-economic position (SEP). RESULTS: Delivery by Caesarean section accounted for 27% of all births and was not clearly associated with hospitalizations for asthma and other wheezing disorders to 12 years [hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.91 to 1.36] compared to vaginal delivery. Similarly, there were no clear associations to 2 years (HR 1.07, 95% CI 0.83 to 1.38) or 6 years (HR 1.12, 95% CI 0.91 to 1.37), although we cannot rule out residual confounding by SEP. CONCLUSIONS AND CLINICAL RELEVANCE: We cannot rule out an association, but our findings suggest that the observed associations of delivery by Caesarean section with childhood wheezing disorders may vary with setting and may not be biologically mediated. Further studies with different designs are needed to clarify the role of the microbiome and mode of delivery in the aetiology of asthma and other childhood wheezing disorders.

Hong Kong College of Physicians Position Statement and Recommendations on the 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension Guidelines for the Management of Arterial Hypertension.

The American College of Cardiology/American Heart Association released guidelines for the prevention, detection, evaluation, and management of high blood pressure (BP) in adults in 2017. In 2018, the European Society of Cardiology (ESC)/European Society of Hypertension (ESH) published new guidelines for the management of arterial hypertension. Despite the many similarities between these two guidelines, there are also major differences in the guidelines in terms of diagnosis and treatment of hypertension. A working group of the Hong Kong College of Physicians (HKCP) convened and conducted a focused discussion on important issues of public interest, including classification of BP, BP measurement, thresholds for initiation of antihypertensive medications, BP treatment targets, and treatment strategies. The HKCP concurs with the 2018 ESC/ESH guideline on BP classification, which defines hypertension as office systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg. The HKCP also acknowledges the growing evidence of home BP monitoring and ambulatory BP monitoring in the diagnosis and monitoring of hypertension and endorses the wider use of both methods. The HKCP also supports the direction of a risk-based approach for initiation of antihypertensive medications and the specification of a treatment target range for both systolic and diastolic BP with consideration of different age-groups and specific disease subgroups. Non-pharmacological interventions are crucial, both at the societal and individual patient levels. The recent guideline publications provide good opportunities to increase public awareness of hypertension and encourage lifestyle modifications among the local population.

Prevalence and impact of vitamin D insufficiency in southern Chinese adults.

INTRODUCTION: Vitamin D is a vital element for bone health but the problem of vitamin D deficiency is underestimated in Hong Kong. METHODS: Serum 25(OH)D and parathyroid hormone (PTH) levels were evaluated in 382 community dwelling Chinese adults >50 years for their relation with bone mineral density (BMD) and risks of osteoporotic fractures and falls. RESULTS: The mean age of the subjects was 69 +/- 9 years. The mean 25(OH)D level was 28.3 +/- 10.8 ng/ml with 62.8% of the subjects having levels <30 ng/ml. 6.3% of the subjects had elevated PTH levels. A curvilinear relation between serum PTH and 25(OH)D was found, with PTH starting to increase when 25(OH)D level fell below 30 ng/ml (r = -0.233, p < 0.05). Although subjects with vitamin D <30 ng/ml had significantly lower BMD, only sex, age and PTH but not 25(OH)D were predictors of BMD at the spine and hip. Subjects with elevated PTH levels had a 2.92-fold increased risk of falls and 2.94-fold increased risk of fractures at the hip and spine. CONCLUSIONS: Vitamin D insufficiency and its complication of secondary hyperparathyroidism is common even in subtropical region and is an important risk factor for low bone mass, falls and fractures.

Cohort Profile: Hong Kong Department of Health Elderly Health Service Cohort.

The Department of Health Elderly Health Service Cohort in Hong Kong was set up to promote understanding of ageing in a global context, to exploit the role of Hong Kong as a sentinel for populations currently experiencing very rapid economic development, to provide a developed non-Western 'social laboratory' where empirically derived hypotheses can be tested and to leverage the different patterns of common chronic diseases between East and West to generate novel hypotheses about their determinants. The initial cohort enrolled from July 1998 to the end of December 2001 includes 66 820 people aged 65 years or older, forming about 9% of the population of this age. A comprehensive health assessment was made at enrollment and then repeated regularly on an ongoing basis. The health assessment included a comprehensive assessment of lifestyle, social circumstances, physical health and mental health, including an assessment of cognition and depressive symptoms. Health services use and deaths have been obtained by record linkage and confirmed, where necessary, by telephone interview. Currently, the data are not publicly available; we would welcome collaborations and research proposals.

HLA-B*38:02:01 predicts carbimazole/methimazole-induced agranulocytosis.

Thioamides antithyroid-drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD-induced agranulocytosis is important for clinical management. We performed a genome-wide association study (GWAS) involving 20 patients with ATD-induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single-nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD-induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8-103.7; P = 1.3 × 10(-24)) and replication (OR = 37; 95% CI = 3.7-367.4; P = 9.6 × 10(-7)). HLA-B*38:02:01 was in complete linkage disequilibrium with rs185386680. High-resolution HLA typing confirmed that HLA-B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)-induced agranulocytosis (OR = 265.5; 95% CI = 27.9-2528.0; P = 2.5 × 10(-14)), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA-B*38:02:01 in predicting CMZ/MMI-induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.

Post-genomics and the neutral theory: variation and conservation in the tumor necrosis factor-alpha promoter.

In the post-genomics era, molecular evolutionary geneticists have come to possess the molecular, statistical, and computational tools for estimating the relative importance of selection and random genetic drift in virtually any gene in almost any organism. We have examined single-nucleotide polymorphisms (SNPs) and nucleotide divergence across a region of approximately 1 kb in the promoter of the human tumor necrosis factor alpha (TNF-alpha) gene. TNF-alpha, which plays an important role in lymphocyte biology and in the pathogenesis of infectious and autoimmune diseases, is tightly regulated at the level of transcription through sequence-specific binding of transcription factors to cognate binding sites in a relatively small region of the 5' non-coding region of the gene. Analysis of the promoter region in 207 human chromosomes revealed nine SNPs, none of which were located in regions known to be important in transcriptional activation. Comparison with one promoter sequence in each of seven species of primates revealed 162 nucleotide sites occupied by a monomorphic nucleotide in the human sample but occupied by a different nucleotide in at least one of the primate sequences (a 'fixed human difference'). The fixed human differences were found outside the regions known to be important in transcriptional activation, and their large number suggests that they might be effectively neutral (Ns<<1). With regard to the human SNPs, although the hypothesis Ns approximately 0 cannot be rejected, the sample configurations suggest that the substitutions might be mildly deleterious. We emphasize the analytical insight to be gained from interspecific comparisons: through the interspecific comparisons, 3.1% of the total sequence information yielded 94.7% of the variable nucleotides. This combined approach, using interspecific comparisons and human polymorphism together with data from functional analyses, provides valuable insights into the evolutionary history and regulation of a key gene in the human immune response.

Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer.

UNLABELLED: PET imaging of malignant tumors with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) as a tracer is a noninvasive diagnostic and prognostic tool that measures tumor metabolism. In this study, we assessed the relationships between FDG uptake and the expression of facilitative glucose transporters, the sizes of populations of proliferating cells and infiltrating macrophages in patients with primary non-small cell lung cancers (NSCLC). METHODS: FDG uptake and the expression of five glucose transporters and the proportions of proliferating cell and macrophage populations were studied in paraffin sections from untreated primary lung cancers by immunohistochemistry. The patients were imaged with FDG PET before surgery. RESULTS: All tumors could be detected by FDG PET. Uptake was correlated with tumor size (P = 0.004). FDG uptake was lower in adenocarcinomas (ACs) than in squamous cell carcinomas (SQCs) (P = 0.03) or large cell carcinomas (P = 0.002) [standardized uptake value corrected for lean body mass (SUL) = 5.42 +/- 2.77, 8.04 +/-3.25 and 10.42 +/- 4.54, respectively]. Glut-1 expression was significantly higher than that of any other transporter. All tumors tested (n = 23) were Glut-1-positive (70.8% +/- 26.1% of tumor cell area was positive and staining intensity was 2.8 +/- 1.2). Glut-1 expression was higher in SQCs (78% +/- 17.8% and 3.5 +/-0.6) than in ACs (47.5% +/- 30.3% and 1.6 +/- 1.1; P = 0.044 for positive tumor cell area and P = 0.005 for staining intensity). Proliferating cells constituted 15.3% +/- 13.1% of the cancer cells, and the average number of macrophages was 7.8% +/- 6.3%; neither correlated with FDG uptake. CONCLUSION: In this population of patients with NSCLC, Glut-1 is the major glucose transporter expressed. Both FDG uptake and Glut-1 expression appear to be associated with tumor size. No association was found between FDG uptake and either macrophage or proliferative cell populations.

Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: I. Are inflammatory cells important?

UNLABELLED: To investigate the contribution of various tumor components to tumor [3H]FDG uptake, the size of proliferative cell and macrophage populations and the extent of necrosis, inflammatory infiltration and granulation tissue formation were evaluated in syngeneic rat mammary cancers (RMC) grown in immunocompetent rats, an animal tumor model that closely mimics human breast carcinoma. METHODS: Tissue components of breast cancers grown in female Lewis rats (n = 6) were identified histologically and immunohistochemically. Tracer uptake was studied by quantitative autoradiography 2 hr after an intravenous injection of 100 muCi [3H]FDG. RESULTS;: RMC tumors were glandular, with small foci of necrosis and were surrounded by a thin layer of granulation tissue. Tumors retained approximately 4% of the injected FDG dose (1.9 +/- 0.27 muCi/g). Macrophages numbered 0.5% of total cancer cells (1.2 +/- 1.0 of 246 +/- 77) and 18.0% +/- 3.9% of the nuclei of cancer cells were proliferating cell nuclear antigen (PCNA) positive (52 +/- 27 of 293 +/- 55). FDG uptake (in apparent disintegrations per minute per microgram of protein) in the cancer cell was 47.3 +/- 5.6, with the highest uptake in foci of high tumor cell density (82.1 +/- 6.3). Lower levels of FDG uptake were found in necrotic areas (19.8 +/- 22.9), granulation tissue (26.9 +/- 9.2) and areas of inflammatory infiltration (20.5 +/- 15.5). CONCLUSION: These data suggest that FDG-PET imaging of untreated breast cancer mainly reflects tracer uptake in cancer cells.

Intratumoral distribution of tritiated-FDG in breast carcinoma: correlation between Glut-1 expression and FDG uptake.

UNLABELLED: Increased expression of glucose transporters is frequently associated with transformation and is often found in malignant tumors. To assess the relationship between cellular glucose transporter Glut-1 (brain/erythrocyte) and FDG uptake in malignant tumors we studied the expression of Glut-1 and 3H-FDG uptake in a syngeneic rat mammary cancer (RMC), an animal tumor model that closely mimics human breast carcinoma. METHODS: Tumors of 1-9 RMT cell line were grown in female Lewis rats and were studied by immunoperoxidase staining with anti-Glut-1 antibodies, macro- and microautoradiography and densitometry following intravenous injection of 3H-FDG. RESULTS: Most of the cancer cells contained Glut-1 positive cytoplasmic granules. Cells with strongly stained cell membrane were mainly observed in areas of intensive intraductal proliferation and high tumor cell density. No staining was observed in necrotic areas, connective tissue stroma or granulation tissue. FDG uptake in areas of high cancer cell density was consistently higher than average tumor uptake. Silver grain counts were 31 +/- 8/0.023 mm2 in regions of viable cancer cells, and were higher as compared to 10 +/-7 counted in necrotic or 8 +/- 8 in connective tissue areas (p = 0.0001). Densitometry of the autoradiograms and of the histochemically stained consecutive sections showed positive correlation between estimates of FDG uptake and the intensity of staining of the Glut-1 antigen (r=0.3-0.6; p=0.0001). CONCLUSION: Our results demonstrate significant positive correlation between the expression of the facilitative glucose transporter Glut-1 and FDG accumulation in viable cancer cells in the syngeneic rat breast cancer. They suggest that the regulation of FDG uptake may be mediated by Glut-1 and the heterogeneous expression of Glut-1 and tracer uptake may reflect localized variations in the metabolic conditions.

Tardive dystonia in Chinese.

Three Chinese patients with the under-recognized condition of tardive dystonia are described. This is a physically and socially handicapping complication of neuroleptic treatment. A past history of acute dystonia does not appear to predict the future development of tardive dystonia. The need for judicious indication of neuroleptics is emphasised.

Acute hypoxic exposure affects gamete quality and subsequent fertilization success and embryonic development in a serpulid polychaete.

Hypoxia likely compromises the reproductive success of those marine organisms carrying out external fertilization because their gametes and embryos are inevitably exposed to the external environment. Hydroides elegans, a dominant serpulid polychaete in Hong Kong waters, can spawn throughout the year but the number of recruits drops during summer when hypoxia commonly occurs. This study attempted to explain such observation by investigating the gamete quality, including sperm motility, egg size, complexity and viability, after 1-h hypoxic exposure (1 mg O2 l(-1)). In addition, how gamete quality affects fertilization success and embryonic development was examined. After 1-h hypoxic exposure, sperm motility was significantly reduced, compromising fertilization success. Although the eggs remained viable, more malformed embryos and retarded embryonic development were observed. We interpreted that the harmful effect of hypoxia on embryonic development was attributed to the teratogenicity and induced oxidative stress, ultimately causing the reduction in recruitment during summer.

Effects of hypoxia on biofilms and subsequently larval settlement of benthic invertebrates.

Biofilms on submerged surfaces are important in determining larval settlement of most marine benthic invertebrates. We investigated if exposure of biofilms to hypoxia would alter the larval settlement pattern and result in a shift in benthic invertebrate community structure in the field. Biofilms were first exposed to hypoxia or normoxia in laboratory microcosms for 7 days, and then deployed in the field for another 7 days to allow for larval settlement and recruitment to occur. Using terminal-restriction fragment length polymorphism of the 16S rRNA gene, this study showed that hypoxia altered the biofilm bacterial community composition, and the difference between the hypoxic and normoxic treatments increased with the time of exposure period. This study also demonstrated significantly different benthic invertebrate community structures as a result of biofilm exposure to hypoxia and that the hypoxic and normoxic treatments were dominated by Hydroides sp. and Folliculina sp., respectively.

Effect of parental hypoxic exposure on embryonic development of the offspring of two serpulid polychaetes: Implication for transgenerational epigenetic effect.

Sperm production and motility, fecundity, and egg size, complexity and viability of serpulid polychaetes Hydroides elegans and Hydroides diramphus after 2-week treatment to hypoxia (2 mg O2 l(-1)) was compared with those under normoxia (6 mg O2 l(-1)). Despite reduced fecundity, the effect of parental hypoxic exposure on gamete quality was not discernible for both species. However, regardless of their subsequent dissolved oxygen environment, eggs spawned by H. elegans after hypoxic exposure were found to have lower fertilization success, slower embryonic development and a significantly higher yield of malformed embryos than those with a parental normoxic treatment. In contrast, neither fertilization success nor rate of embryonic development was affected for H. diramphus. The results implied that hypoxia was a potential stress reducing the recruitment of H. elegans through non-adaptive epigenetic effect, whereas H. diramphus was a more tolerant species to survive hypoxic events.

Hypoxia induces abnormal larval development and affects biofilm-larval interaction in the serpulid polychaete Hydroides elegans.

Hydroides elegans, a worldwide fouling polychaete, can spawn throughout the year, but its recruitment drops during summer when hypoxia prevails. Here, the influence of hypoxia on larval development and settlement of H. elegans was investigated. Results showed that larval development was compromised at 1mg O2 l(-1) with a lower proportion of competent larvae and a higher proportion of malformed larvae, probably due to reduction in clearance rate. Regarding larval settlement, although most of the larvae were reluctant to settle at 1mg O2 l(-1), regardless of the biofilm nature, they settled quickly within 24h in response to the resumption of dissolved oxygen. Furthermore, only about 5% of the larvae settled on the biofilms developed under hypoxia, regardless of dissolved oxygen levels of the seawater. The delayed larval development and potential alteration of biofilm nature owing to hypoxia explained why the recruitment of H. elegans declines during summer.

Heterogeneity in MYC-induced mammary tumors contributes to escape from oncogene dependence.

A hallmark of human cancer is heterogeneity, reflecting the complex series of changes resulting in the activation of oncogenes coupled with inactivation of tumor suppressor genes. Breast cancer is no exception and indeed, many studies have revealed considerable complexity and heterogeneity in the population of primary breast tumors and substantial changes in a recurrent breast tumor that has acquired metastatic properties and drug resistance. We have made use of a Myc-inducible transgenic mouse model of breast cancer in which elimination of Myc activity following tumor development initially leads to a regression of a subset of tumors generally followed by de novo Myc-independent growth. We have observed that tumors that grow independent of Myc expression have gene profiles that are distinct from the primary tumors with characteristics indicative of an epithelial-mesenchymal transition (EMT) phenotype. Phenotypic analyses of Myc-independent tumors confirm the acquisition of an EMT phenotype suggested to be associated with invasive and migratory properties in human cancer cells. Further genomic analyses reveal mouse mammary tumors growing independent of myc have a higher probability of exhibiting a gene signature similar to that observed for human 'tumor-initiating' cells. Collectively, the data reveal genetic alterations that underlie tumor progression and an escape from Myc-dependent growth in a transgenic mouse model that can provide insights to what occurs in human cancers as they acquire drug resistance and metastatic properties.

A role for Myc in facilitating transcription activation by E2F1.

Previous work has demonstrated that E2F proteins regulate the expression of various genes encoding proteins essential for DNA replication and cell-cycle progression. E2F1 in particular is required for the initial entry to the cell cycle from a quiescent state and is required for the activation of other E2F genes. Other work has demonstrated a role for the Myc transcription factor in the activation of a large number of genes associated with cell growth, including E2F genes. We now show that Myc is required to allow the interaction of the E2F1 protein with the E2F gene promoters. As such, Myc thus provides a link between the development of a growth-competent state during the initial stage of G(1) and the activation of genes essential for DNA replication at G(1)/S.

Olfactory ensheathing cells are attracted to, and can endocytose, bacteria.

Olfactory ensheathing cells (OECs) have been shown previously to express Toll-like receptors and to respond to bacteria by translocating nuclear factor-kappaB from the cytoplasm to the nucleus. In this study, we show that OECs extended significantly more pseudopodia when they were exposed to Escherichia coli than in the absence of bacteria (p=0.019). Co-immunoprecipitation showed that E. coli binding to OECs was mediated by Toll-like receptor 4. Lyso-Tracker, a fluorescent probe that accumulates selectively in lysosomes, and staining for type 1 lysosome-associated membrane proteins demonstrated that endocytosed FITC-conjugated E. coli were translocated to lysosomes. They appeared to be subsequently broken down, as shown by transmission electron microscopy. No obvious adherence to the membrane and less phagocytosis was observed when OECs were incubated with inert fluorescent microspheres. The ability of OECs to endocytose bacteria supports the notion that OECs play an innate immune function by protecting olfactory tissues from bacterial infection.