Development of a prediction score (ThyroCOVID) for identifying abnormal thyroid function in COVID-19 patients.

PURPOSE: Thyroid dysfunction in COVID-19 carries clinical and prognostic implications. In this study, we developed a prediction score (ThyroCOVID) for abnormal thyroid function (TFT) on admission amongst COVID-19 patients. METHODS: Consecutive COVID-19 patients admitted to Queen Mary Hospital were prospectively recruited during July 2020-May 2021. Thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured on admission. Multivariable logistic regression analysis was performed to identify independent determinants of abnormal TFTs. ThyroCOVID was developed based on a clinical model with the lowest Akaike information criteria. RESULTS: Five hundred and forty six COVID-19 patients were recruited (median age 50 years, 45.4% men, 72.9% mild disease on admission). 84 patients (15.4%) had abnormal TFTs on admission. Patients with abnormal TFTs were more likely to be older, have more comorbidities, symptomatic, have worse COVID-19 severity, higher SARS-CoV-2 viral loads and more adverse profile of acute-phase reactants, haematological and biochemical parameters. ThyroCOVID consisted of five parameters: symptoms (malaise), comorbidities (ischaemic heart disease/congestive heart failure) and laboratory parameters (lymphocyte count, C-reactive protein, and SARS-CoV-2 cycle threshold values). It was able to identify abnormal TFT on admission with an AUROC of 0.73 (95% CI 0.67-0.79). The optimal cut-off of 0.15 had a sensitivity of 75.0%, specificity of 65.2%, negative predictive value of 93.5% and positive predictive value of 28.1% in identifying abnormal TFTs on admission amongst COVID-19 patients. CONCLUSION: ThyroCOVID, a prediction score to identify COVID-19 patients at risk of having abnormal TFT on admission, was developed based on a cohort of predominantly non-severe COVID-19 patients.

Potential role of fibroblast growth factor 21 in the deterioration of bone quality in impaired glucose tolerance.

PURPOSE: Findings on trabecular bone score (TBS), an index of bone quality, have been reported in prediabetes defined by impaired fasting glucose or HbA1c. Here, we assessed the bone mineral density (BMD) and TBS in prediabetes individuals with impaired glucose tolerance (IGT), and investigated the association of these bone parameters with serum levels of fibroblast growth factor 21 (FGF21), a hormone implicated in bone metabolism and with higher levels in IGT. METHODS: Chinese postmenopausal women aged 55-80 years, without diabetes, were recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study in 2016-2018. Normal glucose tolerance (NGT) was defined by fasting glucose < 5.6 mmol/L and 2-h plasma glucose (2hG) < 7.8 mmol/L, and IGT by 2hG 7.8-11 mmol/L. Serum levels of FGF21 and other bone metabolism regulators were measured. Insulin sensitivity was assessed by the Matsuda index. Independent determinants of TBS were evaluated using multivariable stepwise linear regression. RESULTS: 173 individuals with NGT and 73 with IGT were included. TBS was lower in those with IGT compared to those with NGT, while BMD was comparable. Individuals with IGT had significantly higher serum FGF21 levels, which in turn showed an independent inverse relationship with TBS, attenuated after inclusion of the Matsuda index. Serum FGF21 levels, however, did not correlate with BMD. CONCLUSION: Among Chinese postmenopausal women, bone quality was worse in IGT, despite comparable bone density. FGF21 levels showed a significant independent inverse relationship with TBS, partly attributed to insulin resistance. Whether FGF21 contributes to the impaired bone quality in IGT remains speculative.

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.

Influence of bariatric surgery on weight reduction and control of chronic disease among obese patients in Malaysia.

INTRODUCTION: This study was designed to determine the influence of bariatric surgery on changes in the body mass index (BMI), and the control of diabetes, hypertension and dyslipidaemia among obese patients in Malaysia. MATERIALS AND METHODS: This was a retrospective cohort study undertaken at a public tertiary care centre in the state of Perak, Malaysia. Information of obese patients who underwent bariatric surgery was obtained from their medical records. The changes in the BMI, HbA1C, systolic and diastolic blood pressure (SBP and DBP), and lipid levels between three months before and after the surgery were assessed. RESULTS: The patients (n=106) were mostly Malay (66.0%), had at least one comorbidity (61.3%), and had a mean age of 40.38±11.75 years. Following surgery, the BMI of the patients was found to reduce by 9.78±5.82kg/m2. For the patients who had diabetes (n=24) and hypertension (n=47), their mean HbA1C, SBP and DBP were also shown to reduce significantly by 2.02±2.13%, 17.19±16.97mmHg, and 11.45±12.63mmHg, respectively. Meanwhile, the mean total cholesterol, triglyceride and low-density lipoprotein levels of those who had dyslipidaemia (n=21) were, respectively, lowered by 0.91±1.18mmol/L, 0.69±1.11mmol/L and 0.47±0.52mmol/L. CONCLUSION: The findings suggest that in addition to weight reduction, bariatric surgery is helpful in improving the diabetes, hypertension and dyslipidaemia control among obese patients. However, a large-scale trial with a control group is required to verify our findings.

Annual direct medical costs associated with diabetes-related complications in the event year and in subsequent years in Hong Kong.

AIM: To develop models to estimate the direct medical costs associated with diabetes-related complications in the event year and in subsequent years. METHODS: The public direct medical costs associated with 13 diabetes-related complications were estimated among a cohort of 128 353 people with diabetes over 5 years. Private direct medical costs were estimated from a cross-sectional survey among 1825 people with diabetes. We used panel data regression with fixed effects to investigate the impact of each complication on direct medical costs in the event year and subsequent years, adjusting for age and co-existing complications. RESULTS: The expected annual public direct medical cost for the baseline case was US$1,521 (95% CI 1,518 to 1,525) or a 65-year-old person with diabetes without complications. A new lower limb ulcer was associated with the biggest increase, with a multiplier of 9.38 (95% CI 8.49 to 10.37). New end-stage renal disease and stroke increased the annual medical cost by 5.23 (95% CI 4.70 to 5.82) and 5.94 (95% CI 5.79 to 6.10) times, respectively. History of acute myocardial infarction, congestive heart failure, stroke, end-stage renal disease and lower limb ulcer increased the cost by 2-3 times. The expected annual private direct medical cost of the baseline case was US$187 (95% CI 135 to 258) for a 65-year-old man without complications. Heart disease, stroke, sight-threatening diabetic retinopathy and end-stage renal disease increased the private medical costs by 1.5 to 2.5 times. CONCLUSIONS: Wide variations in direct medical cost in event year and subsequent years across different major complications were observed. Input of these data would be essential for economic evaluations of diabetes management programmes.

Pre-ß1 HDL in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Pre-ß1 HDL, being a major acceptor of free cholesterol from cells, plays an important role in reverse cholesterol transport. This study was performed to determine whether abnormalities in pre-ß1 HDL concentration were present in type 2 diabetes irrespective of their HDL-cholesterol levels, and the impact on cholesterol efflux. METHODS: 640 type 2 diabetic patients with or without cardiovascular disease (CVD) and 360 non-diabetic controls matched for serum HDL-cholesterol levels were recruited. Plasma pre-ß1 HDL was measured by ELISA, and cholesterol efflux to serum, mediated by ATP-binding cassette transporter A1 (ABCA1), was determined by measuring the transfer of [3H]cholesterol from cultured cells expressing ABCA1 to the medium containing the tested serum. RESULTS: Despite the diabetic subjects having matched HDL-cholesterol and total apoA1 as controls, plasma pre-ß1 HDL was significantly reduced in both male (p < 0.01) and female diabetic patients (p < 0.05), and patients with CVD had the lowest pre-ß1 HDL level. Serum capacity to induce ABCA1-mediated cholesterol efflux was impaired in the diabetic group (p < 0.01) and cholesterol efflux correlated with pre-ß1 HDL (Pearson's r = 0.38, p < 0.01), and this association remained significantly even after controlling for age, gender, body mass index, diabetes status, smoking, apoA1, triglyceride and LDL. CONCLUSIONS: Plasma pre-ß1 HDL level was significantly decreased in type 2 diabetes and was associated with a reduction in cholesterol efflux mediated by ABCA1. Our data would suggest that low pre-ß1 HDL might cause impairment in reverse cholesterol transport in type 2 diabetes.

Coherent chemical kinetics as quantum walks. I. Reaction operators for radical pairs.

Classical chemical kinetics uses rate-equation models to describe how a reaction proceeds in time. Such models are sufficient for describing state transitions in a reaction where coherences between different states do not arise, in other words, a reaction that contains only incoherent transitions. A prominent example of a reaction containing coherent transitions is the radical-pair model. The kinetics of such reactions is defined by the so-called reaction operator that determines the radical-pair state as a function of intermediate transition rates. We argue that the well-known concept of quantum walks from quantum information theory is a natural and apt framework for describing multisite chemical reactions. By composing Kraus maps that act only on two sites at a time, we show how the quantum-walk formalism can be applied to derive a reaction operator for the standard avian radical-pair reaction. Our reaction operator predicts the same recombination dephasing rate as the conventional Haberkorn model, which is consistent with recent experiments [K. Maeda et al., J. Chem. Phys. 139, 234309 (2013)], in contrast to previous work by Jones and Hore [J. A. Jones and P. J. Hore, Chem. Phys. Lett. 488, 90 (2010)]. The standard radical-pair reaction has conventionally been described by either a normalized density operator incorporating both the radical pair and reaction products or a trace-decreasing density operator that considers only the radical pair. We demonstrate a density operator that is both normalized and refers only to radical-pair states. Generalizations to include additional dephasing processes and an arbitrary number of sites are also discussed.

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.

Serum calcium and incident diabetes: an observational study and meta-analysis.

UNLABELLED: The study aimed to prospectively evaluate if serum calcium is related to diabetes incidence in Hong Kong Chinese. The results showed that serum calcium has a significant association with increased risk of diabetes. The result of meta-analysis reinforced our findings. INTRODUCTION: This study aimed to evaluate the association of serum calcium, including serum total calcium and albumin-corrected calcium, with incident diabetes in Hong Kong Chinese. METHODS: We conducted a retrospective cohort study in 6096 participants aged 20 or above and free of diabetes at baseline. Serum calcium was measured at baseline. Incident diabetes was determined from several electronic databases. We also searched relevant databases for studies on serum calcium and incident diabetes and conducted a meta-analysis using fixed-effect modeling. RESULTS: During 59,130.9 person-years of follow-up, 631 participants developed diabetes. Serum total calcium and albumin-corrected calcium were associated with incident diabetes in the unadjusted model. After adjusting for demographic and clinical variables, the association remained significant only for serum total calcium (hazard ratio (HR), 1.32 (95 % confidence interval (CI), 1.02-1.70), highest vs. lowest quartile). In a meta-analysis of four studies including the current study, both serum total calcium (pooled risk ratio (RR), 1.38 (95 % CI, 1.15-1.65); I (2) = 5 %, comparing extreme quantiles) and albumin-corrected calcium (pooled RR, 1.29 (95 % CI, 1.03-1.61); I (2) = 0 %, comparing extreme quantiles) were associated with incident diabetes. Penalized regression splines showed that the association of incident diabetes with serum total calcium and albumin-correlated calcium was non-linear and linear, respectively. CONCLUSIONS: Elevated serum calcium concentration is associated with incident diabetes. The mechanism underlying this association warrants further investigation.

Genetics of Apparently Sporadic Pheochromocytoma and Paraganglioma in a Chinese Population.

Identification of germline mutation in patients with apparently sporadic pheochromocytomas and paragangliomas is crucial. Clinical indicators, which include young age, bilateral or multifocal, extra-adrenal, malignant, or recurrent tumors, predict the likelihood of harboring germline mutation in Caucasian subjects. However, data on the prevalence of germline mutation, as well as the applicability of these clinical indicators in Chinese, are lacking. We conducted a cross-sectional study at a single endocrine tertiary referral center in Hong Kong. Subjects with pheochromocytomas and paragangliomas were evaluated for the presence of germline mutations involving 10 susceptibility genes, which included NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, TMEM 127, MAX, and FH genes. Clinical indicators were assessed for their association with the presence of germline mutations. Germline mutations, 2 being novel, were found in 24.4% of the 41 Chinese subjects recruited and 11.4% among those with apparently sporadic presentation. The increasing number of the afore-mentioned clinical indicators significantly correlated with the likelihood of harboring germline mutation in one of the 10 susceptibility genes. (r=0.757, p=0.026). The presence of 2 or more clinical indicators should prompt genetic testing for germline mutations in Chinese subjects. In conclusion, our study confirmed that a significant proportion of Chinese subjects with apparently sporadic pheochromocytoma and paraganglioma harbored germline mutations and these clinical indicators identified from Caucasians series were also applicable in Chinese subjects. This information will be of clinical relevance in the design of appropriate genetic screening strategies in Chinese populations.

Depression, anxiety and stress among patients with diabetes in primary care: A cross-sectional study.

BACKGROUND: The incidence of diabetes mellitus is ever increasing. Individuals with diabetes mellitus may have concurrent mental health disorders and are shown to have poorer disease outcomes. The objectives of this study were to determine the prevalence of depression, anxiety and stress (DAS) in diabetes patients aged 20 years or more in the primary care setting. METHODS: This was a cross-sectional study involving the use of self-administered questionnaire conducted in eight primary care private and government clinics in Pulau Pinang and Melaka, Malaysia. The validated DASS-21 questionnaire was used as a screening tool for the symptoms of DAS. Prior permission was obtained from the patients and, clearance from ethical committee was obtained before the start of the study. Data analysis was done using SPSS statistical software. RESULTS: A total of 320 patients with diabetes from eight centres were enrolled via convenience sampling. Sample size was calculated using the Kish's formula. The prevalence of DAS among patients with diabetes from our study was 26.6%, 40% and 19.4%, respectively. Depression was found to be significantly associated with marital status and family history of DAS; anxiety was significantly associated with monthly household income, presence of co-morbidities and family history of DAS; and stress was significantly associated with occupation and family history of DAS. CONCLUSION: The prevalence of DAS was higher in patients with diabetes compared with the general community. We recommend to routinely screen all patients with diabetes using the DASS-21 questionnaire because it is easy to perform and inexpensive.

Multiple regression analysis in modeling of columnar ozone in Peninsular Malaysia.

This study aimed to predict monthly columnar ozone (O3) in Peninsular Malaysia by using data on the concentration of environmental pollutants. Data (2003-2008) on five atmospheric pollutant gases (CO2, O3, CH4, NO2, and H2O vapor) retrieved from the satellite Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY) were employed to develop a model that predicts columnar ozone through multiple linear regression. In the entire period, the pollutants were highly correlated (R = 0.811 for the southwest monsoon, R = 0.803 for the northeast monsoon) with predicted columnar ozone. The results of the validation of columnar ozone with column ozone from SCIAMACHY showed a high correlation coefficient (R = 0.752-0.802), indicating the model's accuracy and efficiency. Statistical analysis was utilized to determine the effects of each atmospheric pollutant on columnar ozone. A model that can retrieve columnar ozone in Peninsular Malaysia was developed to provide air quality information. These results are encouraging and accurate and can be used in early warning of the population to comply with air quality standards.

Possible FRAX-based intervention thresholds for a cohort of Chinese postmenopausal women.

SUMMARY: A total of 2,266 postmenopausal Chinese women were followed for 4.5 years to determine the incidence of new fractures. The positive predictive value, negative predictive value, sensitivity and specificity of different treatment strategies were compared. Using a fixed optimal threshold calculated from receiver operating characteristics (ROC) curve had the highest sensitivity but lowest specificity. INTRODUCTION: There is no specific intervention threshold based on FRAX to guide treatment for Asian populations. This prospective study sought to determine the impact of applying different intervention thresholds to a cohort of Chinese postmenopausal women. METHODS: This study was part of the Hong Kong Osteoporosis Study. A total of 2,266 treatment-naïve postmenopausal women underwent clinical risk factor and BMD assessments. The subjects were followed to assess fractures. We calculated the FRAX probability of major osteoporotic fractures corresponding to women with prior fractures but no other clinical risk factors. Different treatment strategies which include treating women with prior fractures, women with age-specific FRAX probability corresponding to those with prior fractures, women with osteoporosis as well as women with FRAX probability above a fixed cut-off based on optimizing sensitivity and specificity on the ROC curve were compared. RESULTS: The mean age at baseline was 62.1 ± 8.5 years, and the mean follow-up time was 4.5 ± 2.8 years. One hundred six new major osteoporotic fractures were reported. An optimal (FRAX, with BMD) cut-off point of 9.95 % was identified. All strategies had negative predictive value of >90 %. Using a fixed cut-off had the highest sensitivity (62.3 %) but lowest specificity (73.5 %) and positive predictive value (10.3 %). Using a fixed cut-off would direct treatment from younger women with lower absolute risk to elderly women with higher absolute risk. CONCLUSION: Targeting only women with prior fractures is unlikely to reduce fracture burden. Other treatment strategies with higher sensitivity need to be considered but they have different shortcomings.

A middle-aged man with increasing body fat.

A 51-year-old man was referred for evaluation of gradual increase in body fat over bilateral arms, chest and abdomen for 6 months. He was a non-smoker and he drank at least four bottles of beer daily since the age of 18. There was no significant past medical history or any family history of obesity or endocrine diseases. Physical examination showed localized large bulk of fat over the neck, both arms and mammary regions, abdomen, and back (Figs and ). The lower limbs and buttock were relatively spared. There was telangiectasia over the face and chest wall, but no palmar erythema nor finger clubbing. The liver span was normal, and the spleen tip was palpated 2 cm below the costal margin. Examination of the cardiovascular, respiratory and neurological system was normal. [Figure: see text] [Figure: see text] Blood tests showed thrombocytopenia (platelet 140 × 10(9) L(-1) [normal: 170-380 × 10(9) L(-1) ]) and liver function derangement (bilirubin 27 µmol L(-1) , ALP 298 U L(-1) , ALT 127 U L(-1) , AST 165 U L(-1) , GGT 1353 U L(-1) , albumin 33 g L(-1) and globulin 42 g L(-1) ). His clotting profile and renal functions were normal. His hepatitis B surface antigen was positive, but his HBV DNA was <60 copies per mL. Fasting glucose was 5.0 mmol L(-1) . HbA1c was 5.6%. His lipid profile was satisfactory with total cholesterol of 2.9 mmol L(-1) , triglycerides 1.0 mmol L(-1) , HDL-C 1.37 mmol L(-1) and LDL-C 1.1 mmol L(-1) . Ultrasound of the abdomen showed normal-sized liver with coarsened liver parenchymal echogenicity. The spleen was enlarged to 14 cm. This middle-aged man suffered from multiple symmetric lipomatosis and alcoholic liver disease. Dual-energy X-ray showed 1746 gm (40.1%), 1498 gm (32.8%) and 8322 gm (26.8%) fat over the left arm, right arm and trunk, respectively. The legs were unaffected with 1703 gm (19.4%) and 1627 gm (17.7%) fat over the left and right sides, respectively. The patient was advised to stop drinking and he declined surgical treatment.

Impact of serum amyloid A on cellular cholesterol efflux to serum in type 2 diabetes mellitus.

OBJECTIVE: Serum amyloid A (SAA) is an acute phase response protein and has apolipoprotein properties. Since type 2 diabetes is associated with chronic subclinical inflammation, the objective of this study is to investigate the changes in SAA level in type 2 diabetic patients and to evaluate the relationship between SAA and the capacity of serum to induce cellular cholesterol efflux via the two known cholesterol transporters, scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G1 (ABCG1). METHODS: 264 patients with type 2 diabetes mellitus (42% with normoalbuminuria, 30% microalbuminuria, and 28% proteinuria) and 275 non-diabetic controls were recruited. SAA was measured by ELISA. SR-BI and ABCG1-mediated cholesterol efflux to serum were determined by measuring the transfer of [(3)H]cholesterol from Fu5AH rat hepatoma cells expressing SR-BI and from human ABCG1-transfected CHO-K1 cells to the medium containing the tested serum respectively. RESULTS: SAA was significantly increased in diabetic patients with incipient or overt nephropathy. Both SR-BI and ABCG1-mediated cholesterol efflux to serum were significantly impaired in all three groups of diabetic patients (p < 0.01). SAA inversely correlated with SR-BI-mediated cholesterol efflux (r = -0.36, p < 0.01) but did not correlate with ABCG1-mediated cholesterol efflux. Stepwise linear regression analysis showed that HDL, the presence or absence of diabetes, and log(SAA) were significant independent determinants of SR-BI-mediated cholesterol efflux to serum. CONCLUSION: SAA was increased in type 2 diabetic patients with incipient or overt nephropathy, and SAA was associated with impairment of SR-BI-mediated cholesterol efflux to serum.

Effect of insulin on the soluble receptor for advanced glycation end products (RAGE).

AIMS: The receptor for advanced glycation end products (RAGE) plays an important role in the pathogenesis of diabetic complications. RAGE transcript splicing generates a number of isoforms, including a full-length membrane-bound receptor and a soluble isoform, endogenous secretory RAGE (esRAGE). Soluble forms of the receptor (sRAGE) can also be formed by ectodomain shedding of the membrane-associated receptor. We have evaluated serum levels of sRAGE and esRAGE in Chinese patients with Type 1 diabetes and investigated the effect of insulin on the generation of esRAGE and sRAGE in vitro. METHODS: Serum sRAGE and esRAGE were measured by ELISA. The in vitro effect of insulin was investigated by incubating THP-1 macrophages with insulin and RAGE isoforms in cell lysate and conditioned media determined. RESULTS: In patients with diabetes, both serum esRAGE and sRAGE were significantly higher than in age-matched healthy subjects without diabetes. In vitro, insulin increased esRAGE and total RAGE isoform expression in cell lysate on a western blot, and reverse transcription-polymerase chain reaction showed an increase in esRAGE and full-length RAGE mRNA. This was accompanied by an increase in esRAGE and sRAGE in cell conditioned media. Pretreatment of THP-1 cells with a general metalloproteinase inhibitor GM6001 significantly reduced the production of sRAGE, suggesting that insulin also increased the cleavage of full-length cell surface RAGE to form sRAGE. CONCLUSIONS: Chinese patients with Type 1 diabetes have higher serum levels of esRAGE and sRAGE. In vitro, insulin not only increases both full-length RAGE and esRAGE expression, but can also stimulate the shedding of sRAGE from the membrane-bound receptor.

A spike-timing-based integrated model for pattern recognition.

During the past few decades, remarkable progress has been made in solving pattern recognition problems using networks of spiking neurons. However, the issue of pattern recognition involving computational process from sensory encoding to synaptic learning remains underexplored, as most existing models or algorithms target only part of the computational process. Furthermore, many learning algorithms proposed in the literature neglect or pay little attention to sensory information encoding, which makes them incompatible with neural-realistic sensory signals encoded from real-world stimuli. By treating sensory coding and learning as a systematic process, we attempt to build an integrated model based on spiking neural networks (SNNs), which performs sensory neural encoding and supervised learning with precisely timed sequences of spikes. With emerging evidence of precise spike-timing neural activities, the view that information is represented by explicit firing times of action potentials rather than mean firing rates has been receiving increasing attention. The external sensory stimulation is first converted into spatiotemporal patterns using a latency-phase encoding method and subsequently transmitted to the consecutive network for learning. Spiking neurons are trained to reproduce target signals encoded with precisely timed spikes. We show that when a supervised spike-timing-based learning is used, different spatiotemporal patterns are recognized by different spike patterns with a high time precision in milliseconds.

Pretransplant Model for End-stage Liver Disease score has no impact on posttransplant survival in living donor liver transplantation.

BACKGROUND: A high Model For End-stage Liver Disease (MELD) score≥25 has been reported to be associated with increased posttransplant mortality and morbidity among patients undergoing living donor liver transplantation (LDLT). We reviewed the results of patients undergoing LDLT at our transplant center for decompensated cirrhosis to determine whether a high MELD impacted posttransplant survival. METHODS: From April 2002 to May 2011, 86-176 patients (49%) who underwent LDLT at our center had the indication of decompensated cirrhosis without hepatocellular carcinoma. Data were expressed in mean values±standard error of the means (range). Patients survival rates were analyzed using Kaplan-Meier method. RESULTS: Among the 86 patients with decompensated cirrhosis: Age was 49±2 (1-68) years and 60 (70%) were of male gender. The causes in 25 (29%) were hepatitis B and 25 (29%) hepatitis C as well as one each for hepatitis B/C and B/D coinfections: 9 (10%), alcoholic cirrhosis. MELD score was 18±1 (range=6-40). In hospital mortality was 6/86 (7%). At 1152±95 (range=7-3317) days posttransplant follow-up 64 (74%) were alive with 1-, 3-, and 5-year survival rates of 84%, 70%, and 70%, respectively. MELD scores did not differ between those who survived and those who died (17.5±8.0 versus 17.8±8.4). No difference was noted in those with MELD<25 or ≥25. In fact, the recipient with the highest MELD score (40) survived. CONCLUSION: A high MELD score had no impact on posttransplant survival among cirrhotic patients undergoing LDLT. It should be considered to be an urgent indication rather than a contraindication to LDLT.

Younger age and presence of macrovascular invasion were independent significant factors associated with poor disease-free survival in hepatocellular carcinoma patients undergoing living donor liver transplantation.

OBJECTIVE: Patients with hepatocellular carcinoma (HCC) exceeding the University of California, San Francisco (UCSF) criteria are normally rejected for cadaveric liver transplants. However, whether they should be allowed to undergo living donor liver transplantation (LDLT) has been controversial. We reviewed the outcome of patients with advanced HCC who underwent LDLT at our center. METHODS: From April 2002 to May 2011, 176 patients underwent LDLT at our center; of these, 77 (44%) had HCC at the explant liver. Patient overall survival and recurrence-free survival (RFS) was analyzed using Kaplan-Meier method. Multivariate analysis was performed by Cox analysis. RESULTS: Age was 56±1 (56, 29-71) years; 62 (80.5%) were male; Model for End-stage Liver Disease Score was 11±1 (9, 6-36), alpha fetoprotein (AFP) was 3683±2019 (69, 3-139,591) ng/L; maximum tumor size was 4.5 (0.5-15) cm. Number or tumor nodules was 5 (1-10), and 32 (42%) had macrovascular invasion diagnosed pretransplant. Eleven (14%) were within UCSF criteria. After follow-up of 953±90 (744, 2-2989) days, 53 (69%) were alive and 48 (62%) were recurrence-free. One-, 3- and 5-year overall survival (OS) and recurrence-free survival (RFS) were 80%, 70%, and 57% and 80%, 65%, and 48%, respectively. Five-year OS and RFS for those within UCSF criteria were both 78% versus 55% and 46% outside UCSF criteria (P=not significant). At multivariate analysis, high AFP, younger age, and macrovascular invasion were associated with both poor RFS. CONCLUSION: In HCC patients exceeding UCSF criteria, a reasonable 5-year overall survival of 55% post-LDLT can be obtained. Patients with HCC exceeding the UCSF criteria, especially in the older age group with no portal vein invasion and lower AFP level, should be actively considered for LDLT.

Association of CDX1 binding site of periostin gene with bone mineral density and vertebral fracture risk.

SUMMARY: Periostin (POSTN) as a regulator of osteoblast differentiation and bone formation may affect susceptibility to osteoporosis. This study suggests POSTN as a candidate gene for bone mineral density (BMD) variation and vertebral fracture risk, which could better our understanding about the genetic pathogenesis of osteoporosis and will be useful in clinic in the future. INTRODUCTION: The genetic determination of osteoporosis is complex and ill-defined. Periostin (POSTN), an extracellular matrix secreted by osteoblasts and a regulator of osteoblast differentiation and bone formation, may affect susceptibility to osteoporosis. METHODS: We adopted a tag-single nucleotide polymorphism (SNP) based association method followed by imputation-based verification and identification of a causal variant. The association was investigated in 1,572 subjects with extreme-BMD and replicated in an independent population of 2,509 subjects. BMD was measured by dual X-ray absorptiometry. Vertebral fractures were identified by assessing vertebral height from X-rays of the thoracolumbar spine. Association analyses were performed with PLINK toolset and imputation analyses with MACH software. The top imputation finding was subsequently validated by genotyping. Interactions between POSTN and another BMD-related candidate gene sclerostin (SOST) were analyzed using MDR program and validated by logistical regression analyses. The putative transcription factor binding with target sequence was confirmed by electrophoretic mobility shift assay (EMSA). RESULTS: Several SNPs of POSTN were associated with BMD or vertebral fractures. The most significant polymorphism was rs9547970, located at the -2,327 bp upstream (P = 6.8 × 10(-4)) of POSTN. Carriers of the minor allele G per copy of rs9547970 had 1.33 higher risk of vertebral fracture (P = 0.007). An interactive effect between POSTN and SOST upon BMD variation was suggested (P < 0.01). A specific binding of CDX1 to the sequence of POSTN with the major allele A of rs9547970 but not the variant G allele was confirmed by EMSA. CONCLUSIONS: Our results suggest POSTN as a candidate gene for BMD variation and vertebral fracture risk.