To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 x 10(-18)). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

Previous research has shown that type 2 diabetes mellitus (T2DM) is associated with an increased risk of cognitive impairment. Patients with impaired cognition often show decreased spontaneous brain activity on resting-state functional magnetic resonance imaging (rs-fMRI). This study used rs-fMRI to investigate changes in spontaneous brain activity among patients with T2DM and to determine the relationship of these changes with cognitive impairment. T2DM patients (n = 29) and age-, sex-, and education-matched healthy control subjects (n = 27) were included in this study. Amplitude of lowfrequency fluctuation (ALFF) and regional homogeneity (ReHo) values were calculated to represent spontaneous brain activity. Brain volume and cognition were also evaluated among these participants. Compared with healthy control subjects, patients with T2DM had significantly decreased ALFF and ReHo values in the occipital lobe and postcentral gyrus. Patients performed worse on several cognitive tests; this impaired cognitive performance was correlated with decreased activity in the cuneus and lingual gyrus in the occipital lobe. Brain volume did not differ between the two groups. The abnormalities of spontaneous brain activity reflected by ALFF and ReHo measurements in the absence of structural changes in T2DM patients may provide insights into the neurological pathophysiology underlying diabetes-associated cognitive decline.

Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1a (HIF-1a) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/ integrin b1 axis. Conclusion: ANGPTL4 is a target gene of HIF-1a and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients. (HEPATOLOGY 2011;54:910-919) Abbreviations: 2ME2, 2-methoxyestradiol; AFP, alpha-fetoprotein; ANGPTL4, angiopoietin-like protein 4; ChIP, chromatin immunoprecipitation; CM, conditioned medium; DFO, deferoxamine mesylate; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HIF-1a, hypoxia-inducible factor 1a; HREs, hypoxia-responsive elements; HUVECs, human umbilical vein endothelial cells; IgG, immunoglobulin G; IL-1b, interleukin-1 beta; IjB-b, inhibitor of nuclear factor kappa B beta; kb, kilobase; LPS, lipopolysaccharide; NF-jB, nuclear factor kappa light-chain enhancer of activated B cells; shRNA, short-hairpin RNA; VCAM-1, vascular cell adhesion molecule-1.From the

BackgroundDepression during pregnancy can be detrimental to both maternal and fetal health outcomes. A cross-sectional study was undertaken, with the goal of determining the prevalence and predicting factors associated with antenatal depressive symptoms during late pregnancy among Chinese women.MethodsParticipants were recruited during bookings for antenatal care at a maternal and child health hospital’s outpatient care clinics. Measurements included the Chinese version of Self-rating Depression Scale, Eysenck Personality Questionnaire, Social Support Rating Scale, and Simplified Coping Strategies Questionnaire.ResultsA total of 292 women participated in this study, with 28.5% prevalence of depressive symptoms. Significant protective predictors were: a younger age (OR = 0.85; 95% Confidence Interval-CI 0.76-0.95), good partner relationship (OR = 0.40; 95% CI 0.17-0.93), preparedness for delivery (OR = 0.36; 95% CI 0.20-0.63), active coping (OR = 0.92; 95% CI 0.89-0.96), and social support (OR = 0.92; 95% CI 0.88-0.97). In contrast, significant risk factors were: a history of miscarriage (OR = 1.86; 95% CI 1.30-2.66), irregular menstrual history (OR = 2.98; 95% CI 1.64-5.40), and financial worries (OR = 2.33; 95% CI 1.27-4.30). Psychosocial risk factors include psychoticism and neuroticism personality traits (OR = 1.06; 95% CI 1.02-1.10 and OR = 1.07; 95% CI 1.04-1.10, respectively), and pregnancy pressures (OR = 1.04; 95% CI 1.02-1.07).ConclusionDepressive symptoms are common in third trimester antenatal clinic attendees. Interventions for early recognition of depression should target older women with a history of miscarriage and financial worries. Intervention strategies could be by providing more social support and promoting active coping strategies. Findings support a recommendation that antenatal services consider integrating screening for depression in routine antenatal care.

Abstractobjective There is a high burden of both diabetes (DM) and tuberculosis (TB) in China, and as DM increases the risk of TB and adversely affects TB treatment outcomes, there is a need for bidirectional screening of the two diseases. How this is best performed is not well determined. In this pilot project in China, we aimed to assess the feasibility and results of screening DM patients for TB within the routine healthcare setting of five DM clinics.method Agreement on how to screen, monitor and record was reached in May 2011 at a national stakeholders meeting, and training was carried out for staff in the five clinics in July 2011. Implementation started in September 2011, and we report on 7 months of activities up to 31 March 2012. DM patients were screened for TB at each clinic attendance using a symptom-based enquiry, and those positive to any symptom were referred for TB investigations.results In the three quarters, 72% of 3174 patients, 79% of 7196 patients and 68% of 4972 patients were recorded as having been screened for TB, resulting in 7 patients found who were already known to have TB, 92 with a positive TB symptom screen and 48 of these newly diagnosed with TB as a result of referral and investigation. All patients except one were started on anti-TB treatment. TB case notification rates in screened DM patients were several times higher than those of the general population, were highest for the five sites combined in the final quarter (774 ⁄ 100 000) and were highest in one of the five clinics in the final quarter (804 ⁄ 100 000) where there was intensive in-house training, special assignment of staff for screening and colocation of services.conclusion This pilot project shows that it is feasible to carry out screening of DM patients for TB resulting in high detection rates of TB. This has major public health and patient-related implications.

DNA methylation plays critical roles in transcriptional regulation and chromatin remodeling. Differentially methylated regions (DMRs) have important implications for development, aging and diseases. Therefore, genome-wide mapping of DMRs across various temporal and spatial methylomes is important in revealing the impact of epigenetic modifications on heritable phenotypic variation. We present a quantitative approach, quantitative differentially methylated regions (QDMRs), to quantify methylation difference and identify DMRs from genome-wide methylation profiles by adapting Shannon entropy. QDMR was applied to synthetic methylation patterns and methylation profiles detected by methylated DNA immunoprecipitation microarray (MeDIP-chip) in human tissues/cells. This approach can give a reasonable quantitative measure of methylation difference across multiple samples. Then DMR threshold was determined from methylation probability model. Using this threshold, QDMR identified 10 651 tissue DMRs which are related to the genes enriched for cell differentiation, including 4740 DMRs not identified by the method developed by Rakyan et al. QDMR can also measure the sample specificity of each DMR. Finally, the application to methylation profiles detected by reduced representation bisulphite sequencing (RRBS) in mouse showed the platform-free and species-free nature of QDMR. This approach provides an effective tool for the high-throughput identification of potential functional regions involved in epigenetic regulation.

OBJECTIVEType 2 diabetes is characterized by insulin resistance, which is involved in the development of Alzheimer disease. This study aims to investigate the relationship between abnormal resting-state brain functional connectivity and insulin resistance in type 2 diabetes. RESEARCH DESIGN AND METHODSA total of 30 patients with type 2 diabetes and 31 healthy well-matched volunteers were prospectively examined. Resting-state brain functional connectivity analysis was used to examine the correlation between the posterior cingulate cortex (PCC) and whole-brain regions. The possible relationships between functional connectivity measures and insulin resistance were evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTSCompared with healthy controls, we observed significantly decreased functional connectivity of the PCC within some selected regions, including the right middle temporal gyrus (MTG), left lingual gyrus, left middle occipital gyrus, and left precentral gyrus; increased functional connectivity of the PCC was detected in the left cerebellum posterior lobe, right superior frontal gyrus, and right middle frontal gyrus. A significant negative correlation was found between the PCC-right MTG connectivity and HOMA-IR in type 2 diabetic patients (P = 0.014; r = 20.446). CONCLUSIONSType 2 diabetic patients develop aberrant functional connectivity of the PCC, which is associated with insulin resistance in selected brain regions. Resting-state connectivity disturbance of PCC-MTG may be a central role for evaluating the cognitive dysfunction in type 2 diabetes.Type 2 diabetes is characterized by insulin resistance, as indicated by chronically increased peripheral insulin levels and concomitantly reduced brain insulin activity (1,2). Insulin modulates numerous metabolic pathways, including those associated with brain cognitive function, such as glucose metabolism, synaptic maintenance, vascular function, tau phosphorylation, and b-amyloid regulation (3-5). Recent longitudinal studies have shown that insulin resistance is associated with an increasing risk of developing into Alzheimer disease (AD) from healthy individuals or type 2 diabetic patients (6,7). Due to the distribution of insulin receptors in

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