The recommendation of re-classification of variants of uncertain significance (VUS) in adult genetic disorders patients.

Since variants of uncertain significance (VUS) reported in genetic testing cannot be acted upon clinically, this classification may delay or prohibit precise diagnosis and genetic counseling in adult genetic disorders patients. Large-scale analyses about qualitatively distinct lines of evidence used for VUS can make them re-classification more accurately. We analyzed 458 Chinese adult patients WES data, within 15 pathogenic evidence PS1, PS2, PM1, PM6 and PP4 were not used for VUS pathogenic classification, meanwhile the PP3, BP4, PP2 were used much more frequently. The PM2_Supporting was used most widely for all reported variants. There were also 31 null variants (nonsense, frameshift, canonical ±1 or 2 splice sites) which were probably the disease-causing variants of the patients were classified as VUS. By analyzed the evidence used for all VUS we recommend that appropriate genetic counseling, reliable releasing of in-house data, allele frequency comparison between case and control, expanded verification in patient family, co-segregation analysis and functional assays were urgent need to gather more evidence to reclassify VUS. We also found adult patients with nervous system disease were reported the most phenotype-associated VUS and the lower the phenotypic specificity, the more reported VUS. This result emphasized the importance of pretest genetic counseling which would make less reporting of VUS. Our result revealed the characteristics of the pathogenic classification evidence used for VUS in adult genetic disorders patients for the first time, recommend a rules-based process to evaluate the pathogenicity of VUS which could provide a strong basis for accurately evaluating the pathogenicity and clinical grade information of VUS. Meanwhile, we further expanded the genetic spectrum and improve the diagnostic rate of adult genetic disorders.

Efficacy and safety of intragastric expandable oral capsules in adults with overweight or obesity: A randomized, double-blind, placebo-controlled trial.

AIM: This trial assessed the efficacy and safety of 2.24 g intragastric expandable capsules twice per day versus placebo for weight management in adults with overweight or obesity. METHODS: This double-blind, placebo-controlled study included adults with a body mass index of at least 24 kg/m2 and no more than 40 kg/m2 . In total, 280 participants were recruited from six hospitals in China and were assigned in a 1:1 ratio to receive 2.24 g oral intragastric expandable capsules or placebo for 24 weeks. Coprimary endpoints were the percentage change in body weight from baseline and the rate of weight reduction of ≥5%, assessed using both the full analysis set and per protocol set. RESULTS: At baseline, the mean body weight was 81.8 kg, and the mean body mass index was 29.4 kg/m2 . The mean body weight change at week 24 was -4.9% with intragastric expandable capsules versus -1.9% with placebo [estimated treatment difference (ETD) -3.0%, 95% confidence interval (CI) -4.1 to -1.9; p < .001] using the full analysis set and -6.1% versus -2.5% (ETD -3.6%, 95% CI -5.0 to -2.3; p < .001), respectively, using the per protocol set. The percentage of participants who had weight loss exceeding 5% was 45.0% in the intragastric expandable capsule group versus 19.7% in the placebo group (ETD 25.3%, 95% CI 14.7-35.9; p < .001) in the full analysis set and 55.9% versus 26.2% (ETD 29.6%, 95% CI 17.1-42.2; p < .001), respectively, in the per protocol set. Waist circumference significantly decreased at week 24 (intragastric expandable capsules vs. placebo: -5.6 ± 8.3 cm vs. -2.9 ± 4.8 cm; p = .003). The most common adverse events associated with the use of intragastric expandable capsules were gastrointestinal disorders (intragastric expandable capsule vs. placebo, 25.0% vs. 21.9%), and most were mild and transient. CONCLUSIONS: In this 24-week trial including participants with overweight or obesity, 2.24 g of intragastric expandable capsules twice daily led to a clinically meaningful reduction in body weight compared with placebo.

Sex disparity of cerebral white matter hyperintensity in the hypertensive elderly: The Shanghai Changfeng study.

White matter hyperintensity (WMH) is associated with vascular hemodynamic alterations and reflects white matter injury. To date, the sex difference of tract-specific WMH and the relationship between high blood pressure (BP) and tract-specific WMH remain unclear. We recruited 515 subjects from the Shanghai Changfeng study (range 53-89 years, mean age 67.33 years). Systolic and diastolic blood pressure (SBP and DBP) were collected and used to calculate pulse pressure (PP). Magnetic resonance T1 and T2 FLAIR images were acquired to measure WMH and calculate WMH index. The ANCOVA test was performed to test the difference between sexes, and the linear regression model was used to examine the associations between BP and WMH index. Men showed higher WMH index than women in all white matter tracts (p < .001, respectively) except for the bilateral superior longitudinal fasciculus (SLF) and its left temporal part (tSLF). High SBP and PP was associated with a lower WMH index on the left corticospinal tract (CST), SLF, tSLF and right cingulum in hippocampus (p ≤ .001, respectively) in women, while high DBP was associated with a higher WMH index on the bilateral CST (left p < .001; right p = .001), left inferior longitudinal fasciculus (p < .001) and inferior fronto-occipital fasciculus (p = .002) in men. Men tend to have more WMH compared to women. A high SBP/PP relates to a lower WMH burden in women. This suggests that women could benefit from higher blood pressure in older age.

Comparison between UK Biobank and Shanghai Changfeng suggests distinct hip morphology may contribute to ethnic differences in the prevalence of hip osteoarthritis.

OBJECTS: Joint morphology is a risk factor for hip osteoarthritis (HOA) and could explain ethnic differences in HOA prevalence. Therefore, we aimed to compare the prevalence of radiographic HOA (rHOA) and hip morphology between the predominantly White UK Biobank (UKB) and exclusively Chinese Shanghai Changfeng (SC) cohorts. METHODS: Left hip iDXA scans were used to quantify rHOA, from a combination of osteophytes (grade ≥1) and joint space narrowing (grade ≥1), and hip morphology. Using an 85-point Statistical Shape Model (SSM) we evaluated cam (alpha angle ≥60°) and pincer (lateral centre-edge angle (LCEA) ≥45°) morphology and acetabular dysplasia (LCEA <25°). Diameter of femoral head (DFH), femoral neck width (FNW), and hip axis length (HAL) were also obtained from these points. Results were adjusted for differences in age, height, and weight and stratified by sex. RESULTS: Complete data were available for 5924 SC and 39,020 White UKB participants with mean ages of 63.4 and 63.7 years old. rHOA prevalence was considerably lower in female (2.2% versus 13.1%) and male (12.0% and 25.1%) SC compared to UKB participants. Cam morphology, rarely seen in females, was less common in SC compared with UKB males (6.3% versus 16.5%). Composite SSM modes, scaled to the same overall size, revealed SC participants to have a wider femoral head compared to UKB participants. FNW and HAL were smaller in SC compared to UKB, whereas DFH/FNW ratio was higher in SC. CONCLUSIONS: rHOA prevalence is lower in Chinese compared with White individuals. Several differences in hip shape were observed, including frequency of cam morphology, FNW, and DFH/FNW ratio. These characteristics have previously been identified as risk factors for HOA and may contribute to observed ethnic differences in HOA prevalence.

A novel model for detecting advanced fibrosis in patients with nonalcoholic fatty liver disease.

AIMS: The study aimed to develop a novel noninvasive model to detect advanced fibrosis based on routinely available clinical and laboratory tests. MATERIALS AND METHODS: A total of 309 patients who underwent liver biopsy were randomly divided into the estimation group (n = 201) and validation group (n = 108). The model was developed using multiple regression analysis in the estimation group and further verified in the validation group. Diagnostic accuracy was evaluated using the receiver operating characteristic (ROC) curve. RESULTS: The model was named NAFLD Fibrosis Index (NFI): -10.844 + 0.046 × age - 0.01 × platelet count + 0.19 × 2h postprandial plasma glucose (PG) + 0.294 × conjugated bilirubin - 0.015 × ALT + 0.039 × AST + 0.109 × total iron binding capacity -0.033 × parathyroid hormone (PTH). The area under the ROC curve (AUC) of NFI was 0.86 (95% CI: 0.79-0.93, p < 0.001) in the estimation group and 0.80 (95% CI: 0.69-0.91, p < 0.001) in the validation group, higher than NFS, FIB4, APRI, and BARD, and similar to FibroScan (NFI AUC = 0.77, 95% CI: 0.66-0.89, p = 0.001 vs. FibroScan AUC = 0.76, 95% CI: 0.62-0.90, p = 0.002). By applying the low cut-off value (-2.756), advanced fibrosis could be excluded among 49.3% and 48% of patients in the estimation group (sensitivity: 93.1%, NPV: 97.9%, specificity: 55.2%, and PPV: 26.0%) and validation group (sensitivity: 81.3%, NPV: 94.2%, specificity: 53.3%, and PPV: 23.2%), respectively, allowing them to avoid liver biopsy. CONCLUSIONS: The study has established a novel model for advanced fibrosis, the diagnostic accuracy of which is superior to the current clinical scoring systems and is similar to FibroScan.

Identification of circulating sphingosine kinase-related metabolites for prediction of type 2 diabetes.

BACKGROUND: Sphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort. METHODS: Levels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study. RESULTS: Comparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859). CONCLUSION: Circulating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.

DS21, a new noninvasive technology, is effective and safe for screening for prediabetes and diabetes in Chinese population.

BACKGROUND: Screening for prediabetes and asymptomatic diabetes is important for preventing development to an irreversible stage. The current diagnosis of prediabetes and diabetes is based on blood glucose or HbA1c (an invasive method). The aim of this study was to assess the efficacy and safety of DS21, a new noninvasive technology, for noninvasive screening for prediabetes and diabetes. METHODS: A total of 939 subjects were divided into a normal control group (NC, n = 308), impaired glucose regulation group (IGR, n = 312), and diabetes (DM) group (n = 319). All subjects underwent the DS21 test, and mean hands-feet, hand, and feet conductance values were analyzed. The diagnostic accuracy of the conductance value was analyzed by receiver-operating characteristic (ROC) curve. RESULTS: The conductance values for hands-feet, hands, and feet in the DM and IGR groups were significantly lower than those in the NC group (all P < 0.01). The area under the ROC curve  (AUCROC) for distinguishing NC/IGR was highest when using hands-feet conductance values (0.766 [95% confidence interval, CI 0.730, 0.803]). However, the AUCROCs of distinguishing NC/abnormal glucose metabolism (AGM, including IGR+DM), non-diabetes (NDM)/DM, and IGR/DM were highest when using conductance values for hands at 0.782 [95% CI 0.752, 0.812], 0.688 [95% CI 0.653, 0.723] and 0.573 [95% CI 0.528, 0.617], respectively (all P < 0.01). Hand conductance of values 75.0 (sensitivity 0.769, specificity 0.660), 77.1 (sensitivity 0.718, specificity 0.695), 68.4 (sensitivity 0.726, specificity 0.555), and 58.1 (sensitivity 0.384, specificity 0.744) were recommended as the screening thresholds for NC/AGM, NC/IGR, NDM/DM, and IGR/DM, respectively. A hand conductance value 66.0 was also recommended to distinguish NC/AGM due to its high sensitivity and high PPV. No adverse events occurred in the test. CONCLUSIONS: DS21 is fast, noninvasive, low cost, reliable and safe, which makes it a feasible device for screening for prediabetes and diabetes, especially in a large population.

The PNPLA3 rs738409 C>G variant interacts with changes in body weight over time to aggravate liver steatosis, but reduces the risk of incident type 2 diabetes.

AIMS/HYPOTHESIS: The rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort. METHODS: The LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4 year changes in body weight on liver steatosis and glucose metabolism. RESULTS: The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2 h post-load blood glucose (PBG) in relation to 4 year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity. CONCLUSIONS/INTERPRETATION: The PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.

The major causes and risk factors of total and cause-specific mortality during 5.4-year follow-up: the Shanghai Changfeng Study.

To investigate the major causes and predictive factors of death in a middle-aged and elderly Chinese population. A total of 6591 residents aged ≥ 45 years from Shanghai Changfeng community were followed up for an average of 5.4 years. The causes of death were coded according to the 10th Revision of International Classification of Diseases. The mortality rate was calculated by person-years of follow up and age-standardized according to the 2010 Chinese census data. Multivariable-adjusted Cox proportional hazards model was performed to investigate the predictors of all-cause and cause-specific mortality. During the total follow-up of 35,739 person-years, 370 deaths were documented (157 from malignant neoplasms, 70 from heart diseases, 68 from cerebrovascular diseases, 75 from other causes). The age-standardized all-cause mortality rate was 798.2 per 100,000 person-years (927.9 among men and 716.7 among women). Results from multivariable analyses showed that aging, diabetes, and osteoporosis at baseline were independent predictors of all-cause mortality, with hazard ratios (HR) of 1.11 (95% CI 1.10-1.13), 1.91 (1.51-2.42), and 1.71 (1.24-2.35), respectively. The population attributable risk percent of diabetes and osteoporosis was 19.7% and 11.7%, respectively. Cigarette smoking was associated with a higher risk of all-cause mortality in men (HR and 95%CI 1.44, 1.01-2.06). In women, diabetes and osteoporosis were related to a higher risk of cardiovascular mortality (3.27, 1.82-5.88 and 1.89, 1.04-3.46, respectively). While in men, osteoporosis was related to a higher risk of malignant neoplasms mortality (2.39, 1.07-5.33). Malignant neoplasms, heart diseases, and cerebrovascular diseases are the leading causes of death. Aging, smoking, underweight, diabetes, and osteoporosis are independent predictors of premature death among middle-aged and elderly Chinese community population. Moreover, there may have been some differences in the causes and predictors of premature death between men and women.

Association of visceral adiposity and its longitudinal increase with the risk of diabetes in Chinese adults: A prospective cohort study.

OBJECTIVE: A Chinese visceral adiposity index (CVAI) was recently established to estimate the visceral fat area in Chinese adults. This study aimed to investigate the risk of incident prediabetes and diabetes in relation to visceral adiposity calculated by CVAI. METHODS: A total of 2558 subjects with normal plasma glucose levels from the Shanghai Changfeng Study were enrolled in a prospective cohort study. The independent associations of basal visceral fat area by CVAI and its longitudinal change with incident prediabetes and diabetes were identified using Cox regression analyses. RESULTS: During an average of 4.4 years of follow-up, 546 (21.3%) and 99 (3.9%) of 2558 nondiabetic subjects developed prediabetes and diabetes, respectively. Visceral fat area by CVAI and its longitudinal increase were independently associated with incident prediabetes and diabetes in Chinese adults. In a multivariable-adjusted regression model, CVAI, as well as its annual change, was the strongest independent predictor of incident prediabetes (HR, 1.383 [1.162-1.647]) and diabetes (HR, 1.607 [1.092-2.364]) compared with other estimates of obesity (BMI and waist circumference). Receiver operating characteristic curve analyses showed that CVAI had better performance than BMI and waist circumference for the prediction of prediabetes and diabetes in Chinese adults. CONCLUSIONS: Visceral adiposity plays a pivotal role in the pathogenesis of diabetes, and the visceral adiposity estimated by CVAI is superior to the traditional estimates of obesity for the prediction of incident prediabetes and diabetes in Chinese adults.

Serum ferritin levels are associated with insulin resistance in Chinese men and post-menopausal women: the Shanghai Changfeng study.

Associations between ferritin and insulin sensitivity have been described in recent studies. The possible association showed conflicting results by sex and menopausal status. We aimed to investigate the cross-sectional association of ferritin levels with insulin resistance and ß-cell function. A total of 2518 participants (1033 men, 235 pre-menopausal women and 1250 post-menopausal women) were enrolled from the Changfeng Study. A standard interview was conducted, as well as anthropometric measurements and laboratory analyses, for each participant. The serum ferritin level was measured using electrochemiluminescence immunoassay. Insulin resistance and ß-cell function indices were derived from a homeostasis model assessment. The results showed that the serum ferritin levels were 250·4 (sd 165·2), 94·6 (sd 82·0) and 179·8 (sd 126·6) ng/ml in the men, pre-menopausal and post-menopausal women, respectively. In fully adjusted models (adjusting for age, current smoking, BMI, waist:hip ratio, systolic blood pressure, diastolic blood pressure, TAG, HDL-cholesterol, LDL-cholesterol, log urine albumin:creatinine ratio, leucocytes, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase), serum ferritin concentrations are significantly associated with insulin resistance in men and post-menopausal females, and the null association was observed in pre-menopausal females. Interestingly, an increased ß-cell function associated with higher ferritin was observed in post-menopausal participants, but not in male participants. In conclusion, these results suggested that elevated serum ferritin levels were associated with surrogate measures of insulin resistance among the middle-aged and elderly male and post-menopausal women, but not in pre-menopausal women.

The prevalence of multiple non-communicable diseases among middle-aged and elderly people: the Shanghai Changfeng Study.

OBJECTIVE: We set out to study the prevalence and combination of multiple non-communicable diseases among middle-aged and elderly people in the Shanghai Changfeng community, China. METHODS: A cross-sectional survey through questionnaire, physical, and laboratory examinations, color ultrasound and DXA was performed on a typical sample of 6038 residents (ages greater than 45-years-old) from the Shanghai Changfeng community between June 2009 and December 2012. RESULTS: The prevalence of chronic diseases (rating from high to low) was as follows: hypertension (55.3%), dyslipidemia (33.5%), diabetes (21.9%), obesity (12.4%), and osteoporosis (9.3%). There were sex-specific and age-specific differences in these diseases. Just less than half (40.5%) the study population suffered from two or more chronic diseases. Hypertension patients were more likely to suffer from obesity, diabetes, dyslipidemia, and risk factors for cardiovascular diseases, but not osteoporosis. The most common combination of multiple diseases was hypertension with dyslipidemia (9.95%) or diabetes (6.61%). CONCLUSION: In the Chinese middle-aged and elderly population, the most common multiple non-communicable diseases, including hypertension, dyslipidemia, diabetes, and obesity should be controlled to prevent cardiovascular disease.

Optimal Vitamin D Status in a Middle-Aged and Elderly Population Residing in Shanghai, China.

BACKGROUND The aim of this study was to investigate the optimal vitamin D status in the middle-aged and elderly population residing in Shanghai, China. MATERIAL AND METHODS A total of 1,829 males and postmenopausal females older than 45 years of age in the Changfeng community of Shanghai were included in this study. The optimal vitamin D level was determined according to the suppression of parathyroid hormone (PTH) and the highest bone mineral density (BMD). Locally weighted scatter plot smoothing (LOWESS) was performed to study the correlations of 25(OH)D with PTH and BMD in the lumbar spine and total hip, adjusting for gender, age, weight, use of calcium and vitamin D supplements, eGFR, smoking status, and alcohol consumption. RESULTS The mean serum 25(OH)D concentration was 48.0±19.2 nmol/L for the whole study population. The circulating PTH was maximally suppressed by the serum 25(OH)D of 55 nmol/L in the total population (60 nmol/L for males and 50 nmol/L for females). The 25(OH)D concentrations corresponding to the highest BMD at lumbar spine (L1-L4) and total hip were 53 nmol/L and 75 nmol/L, respectively, for the whole population. These values were also higher in males than females. CONCLUSIONS The optimal 25(OH)D concentration of 55 nmol/L is sufficient to maintain the bone health and metabolic status in middle-aged and elderly individuals living in Shanghai. Males probably need higher vitamin D concentration than females. There are differences between vitamin D status based on lumbar spine BMD and total hip BMD.

Relationship between non-high-density lipoprotein cholesterol and carotid atherosclerosis in normotensive and euglycemic Chinese middle-aged and elderly adults.

BACKGROUND: We investigate whether non-high-density lipoprotein cholesterol (non-HDL-C) provides a better estimate of cardiovascular risk than other lipid profiles in normotensive and euglycemic middle-aged and elderly adults. METHODS: A total of 512 males and 958 females were enrolled from the Changfeng Study. A standard interview, anthropometric measurements and laboratory analyses were performed for each participant. Bilateral carotid intima-media thicknesses (CIMTs) were measured using ultrasonography, and the presence of carotid plaques was assessed. RESULTS: The mean values of non-HDL-C were 3.4 ± 0.8 mmol/l and 3.6 ± 0.9 mmol/l for male and female subjects, respectively. Compared with female subjects with non-HDL-C in the first quartile, female subjects with non-HDL-C in the fourth quartile had 1.317-fold increased risks for carotid plaques after adjusting for conventional cardiovascular disease (CVD) risk factors and increasing quartiles of all lipid levels. Non-HDL-C was positively associated with the CIMT after adjusting for CVD risk factors in female subjects (ß = 0.062, P = 0.034). CONCLUSIONS: These results suggest that non-HDL-C is independently associated with carotid atherosclerosis in normotensive and euglycemic females.

Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease.

BACKGROUND: We recently demonstrated a positive effect of berberine on nonalcoholic fatty liver disease patients after 16 weeks of treatment by comparing mere lifestyle intervention in type 2 diabetes patients with berberine treatment, which decreased the content of hepatic fat. However, the potential mechanisms of the clinical effects are unclear. We used a lipidomic approach to characterize the state of lipid metabolism as reflected in the circulation of subjects with nonalcoholic fatty liver disease (NAFLD) before and after berberine treatment. METHODS: Liquid chromatography-mass spectrometry evaluated the various lipid metabolites in serum samples obtained from the participants (41 patients in the berberine group and 39 patients in the mere lifestyle intervention group) before and after treatment. RESULTS: A total of 256 serum lipid molecular species were identified and quantified. Both treatments regulated various types of lipids in metabolic pathways, such as free fatty acids, phosphoglycerides and glycerides, in metabolic pathways, but berberine induced a substantially greater change in serum lipid species compared with mere lifestyle intervention after treatment. Berberine also caused obvious differences on ceramides. Berberine treatment markedly decreased serum levels of ceramide and ceramide-1-phosphate. CONCLUSIONS: Berberine altered circulating ceramides, which may underlie the improvement in fatty liver disease. ClinicalTrials.gov NCT00633282, Registered March 3, 2008.

The association of liver fat content and serum alanine aminotransferase with bone mineral density in middle-aged and elderly Chinese men and postmenopausal women.

BACKGROUND: Recent studies have linked non-alcoholic fatty liver disease (NAFLD) to a reduced bone mineral density (BMD). We aimed to detect the quantitative association of liver fat content (LFC) and serum alanine aminotransferase (ALT) with BMD in a middle-aged and elderly Chinese population. METHODS: The lumbar spine, hip and whole body BMDs were measured using dual-energy x-ray absorptiometry (Lunar iDXA, GE Healthcare) in 1659 Chinese (755 men and 1028 postmenopausal women) from Shanghai Changfeng community. Liver fat content was quantified via an ultrasound quantitative method. Multivariate linear regression analyses were carried out to determine the independent association of LFC and serum ALT with BMD and bone metabolic biomarkers. We also attempted to investigate the synergistic association between LFC and ALT as risk factors for bone mineral loss in Chinese. RESULTS: Subjects with higher LFC had significantly lower BMD at all skeletal sites. Univariate correlation analysis showed that both LFC and ALT were inversely associated with BMD at the spine (r = -0.116, P < 0.001 and r = -0.102, P = 0.005), hip (r = -0.095, P = 0.014 and r = -0.075, P = 0.041) and whole body sites (r = -0.134, P < 0.001 and r = -0.164, P < 0.001) in men. After confounders were controlled for, LFC and ALT remained associated with BMD and bone formation biomarkers in men, but not postmenopausal women. When both NAFLD and elevation of ALT were present, there was a significant synergistic worsening of the BMDs at all bone sites. CONCLUSIONS: Liver fat content and serum ALT were inversely correlated with BMD in middle-aged and elderly men. The underlying mechanism might relate to a reduction in osteoblast activity. Elevation of the hepatotoxic biomarker ALT may indicate high risk for osteoporosis in patients with NAFLD.

Serum retinol binding protein 4 is negatively related to estrogen in Chinese women with obesity: a cross-sectional study.

BACKGROUND: The association between serum Retinol Binding Protein 4 (RBP4) and obesity is still controversial. Serum RBP4 levels varies by gender, and estradiol may play a role in the difference. To investigate the participation of sex hormones in the association of RBP4 and obesity in humans, we measured serum RBP4, BMI, and sex hormones in 87 women from the outpatient. METHODS: Eighty-seven subjects of Chinese women origin from the outpatient (aged 40.22 ± 15.54 years) were enrolled. Subjects with diseases affecting the metabolic state or not suitable to participate in this study were excluded. Anthropometrics and laboratory tests, including lipid profile, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2),progesterone (PROG), testosterone (TESTO), and dehydroepiandrosterone (DHEA) were conducted. Serum RBP4 was detected by an enzyme immunoassay kit and validated by quantitative Western blotting. RESULTS: Circulating RBP4 levels were positively associated with BMI, waist circumference, waist-to-hip ratio (WHR), systolic and diastolic (SBP), diastolic blood pressure (DBP), triglycerides (TG), low high-density lipoprotein cholesterol(LDL-c), and testosterone (TESTO) in the total group. While only in obese individuals, serum RBP4 levels were negatively associated with E2. The highest value was in the subjects with both obesity and the low estrogen level. Multiple linear regression analysis revealed that RBP4 correlated independently with TG, TC and insulin in all subjects, TC in non- obese individuals. However, E2 were significantly associated with serum RBP4 only in obese individuals. CONCLUSIONS: RBP4 could be a marker of obesity-related factors; estrogen was negatively related to RBP4 and might be one of the influential factors.

Serum ferritin levels are associated with carotid atherosclerosis in Chinese postmenopausal women: the Shanghai Changfeng Study.

Postmenopausal women are at increased risk of CVD: the increased serum ferritin level may be involved in the pathogenesis. The aim of the present study is to investigate the relationship of ferritin and carotid atherosclerosis in postmenopausal women. A total of 1178 postmenopausal women (mean age, 60·8 years) were enrolled from the Changfeng Study. A standard interview, anthropometric measurements and laboratory analyses were performed for each participant. Bilateral CIMT (carotid intima-media thickness) were measured using ultrasonography, and the presence of carotid plaques was assessed. Serum ferritin was measured using electrochemiluminescence immunoassay. The results showed that serum ferritin was 181·9 (sd 65·8) ng/ml in the postmenopausal women. Multivariate, linear, stepwise regression analysis demonstrated that age (standardised ß = 0·233, P< 0·001), alanine transaminase (standardised ß = 0·194, P< 0·001), log homeostasis model assessment index for insulin resistance (standardised ß = 0·181, P< 0·001), TAG (standardised ß = 0·083, P= 0·003), Hb (standardised ß = 0·080, P= 0·004) and PPG (2-h glucose levels following a 75-g oral glucose challenge) (standardised ß = 0·079, P= 0·004) were independently associated with serum ferritin. Compared with the ferritin level of subjects in the first quartile, that in the fourth quartile had greater CIMT, and higher prevalence of carotid plaque. After adjusting for conventional CVD risk factors, Hb, leucocytes, log urine albumin:creatinine ratio and liver function, the ferritin level of postmenopausal women in the fourth quartile had a 1·587-fold increased risk of carotid plaques relative to those in the lowest quartile. In conclusion, these results suggest that serum ferritin is independently and positively associated with carotid atherosclerosis in postmenopausal women and that ferritin may be implicated in atherosclerosis.

[The clinical value of calcaneus stiffness index calculated by quantitative ultrasound test in screening and diagnosis of osteoporosis].

OBJECTIVE: To evaluate the diagnostic value of quantitative ultrasound test (QUS) in osteoporosis screening by comparing stiffness index (STI) calculated by QUS and bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in Chinese community population. METHODS: A total of 6 105 residents aged 45 years and over from Shanghai Changfeng community were recruited. BMD of lumbar spine (L1-L4) and both femur measured by DXA and calcaneus STI calculated by QUS were observed simultaneously in the same day. The sensitivity, specificity and accuracy of QUS and DXA (gold standard) on the diagnosis of osteoporosis were compared. RESULTS: The prevalence of osteopenia or osteoporosis diagnosed by DXA and QUS was 38.82%, 10.29% and 64.50%, 4.49% respectively. STI was correlated with BMD of spine, left and right femur, respectively with the correlation coefficients of 0.536, 0.574 and 0.570 (all P < 0.001). The sensitivity and specificity of QUS for osteopenia was 86.16% and 47.57% and for osteoporosis was 23.57% and 97.70%. CONCLUSION: STI calculated by QUS had a good correlation with BMD measured by DXA. The high sensitivity and specificity of QUS made it as a diagnostic tool for osteopenia and osteoporosis screening in community health care center.

Serum 25-hydroxyvitamin D levels are associated with carotid atherosclerosis in normotensive and euglycemic Chinese postmenopausal women: the Shanghai Changfeng study.

BACKGROUND: The role of serum 25-hydroxyvitamin D (25 (OH) D) in atherogenesis is unclear. We investigated whether the 25 (OH) D is independently associated with the carotid intima-media thickness (CIMT) and carotid plaques in normotensive and euglycemic postmenopausal women. METHODS: A total of 671 normotensive and euglycemic postmenopausal women (mean age, 58.8 years) were enrolled from the Changfeng Study. A standard interview, anthropometrics measurements and laboratory analyses were performed for each participant. Bilateral CIMTs were measured using ultrasonography, and the presence of carotid plaques was assessed. The serum 25 (OH) D was measured using electrochemiluminescence immunoassay. RESULTS: Serum 25 (OH) D was 43.6 ± 18.2 nmol/L in the postmenopausal women. Compared with subjects with 25 (OH) D in the first, second and third quartiles, subjects with 25 (OH) D in the fourth quartile had decreased CIMT and prevalence of carotid plaque (0.684 ± 0.009 mm vs 0.719 ± 0.009 mm, 0.708 ± 0.009 mm and 0.709 ± 0.009 mm; 10.8% vs 19.0%, 14.8% and 16.8%, respectively). After adjusting for conventional CVD risk factors, PTH, liver and renal function, postmenopausal women with 25 (OH) D in the fourth quartile still had lower CIMT than those in the first, second and third quartiles (p = 0.039) and the subjects in the fourth quartile had a 0.421-fold decreased risk of carotid plaques relative to those in the lowest quartile (95% confidence interval 0.209 to 0.848). CONCLUSIONS: These results suggest serum 25 (OH) D is independently and inversely associated with carotid atherosclerosis in postmenopausal women with normal blood pressure and normal glucose tolerance.