Association Between Night Shift and Hypertension: A Cross-Sectional Study in Chinese Adults.

OBJECTIVE: The purpose of this study was to explore the effect of night-shift work on the risk of hypertension for improving workers' health. METHODS: A total of 10,038 Chinese participants were constituted in the cross-sectional study. Logistic regression and restricted cubic spline were used to estimate the effect of night shift on hypertension. RESULTS: There were higher odds of having hypertension in any night-shift workers (odds ratio [OR], 1.16 [95% confidence interval, 1.03-1.30]) when compared with day workers. Having 5 to 10 night shifts per month were significantly more likely to be hypertensive (OR, 1.19 [95% confidence interval, 1.03-1.38]). The OR for hypertension increased as the number of night shifts increased as the result of the restricted cubic spline. CONCLUSIONS: Our results support the hypothesis that night shift is associated with an elevated risk of hypertension.

FAM9B serves as a novel meiosis-related protein localized in meiotic chromosome cores and is associated with human gametogenesis.

Meiosis is a complex process involving the expression and interaction of numerous genes in a series of highly orchestrated molecular events. Fam9b localized in Xp22.3 has been found to be expressed in testes. However, FAM9B expression, localization, and its role in meiosis have not been previously reported. In this study, FAM9B expression was evaluated in the human testes and ovaries by RT-PCR, qPCR, and western blotting. FAM9B was found in the nuclei of primary spermatocytes in testes and specifically localized in the synaptonemal complex (SC) region of spermatocytes. FAM9B was also evident in the follicle cell nuclei and diffusely dispersed in the granular cell cytoplasm. FAM9B was partly co-localized with SYCP3, which is essential for both formation and maintenance of lateral SC elements. In addition, FAM9B had a similar distribution pattern and co-localization as γH2AX, which is a novel biomarker for DNA double-strand breaks during meiosis. All results indicate that FAM9B is a novel meiosis-associated protein that is co-localized with SYCP3 and γH2AX and may play an important role in SC formation and DNA recombination during meiosis. These findings offer a new perspective for understanding the molecular mechanisms involved in meiosis of human gametogenesis.

Associations of exposure to multiple trace elements with the risk of goiter: A case-control study.

Goiter is one of common endocrine diseases, and its etiology has not been fully elucidated. The changes in trace elements' levels have an important impact on the thyroid. We designed a case-control study, which involved 383 goiter cases and 383 matched controls. We measured these elements in the urine of participants by inductively coupled plasma optical emission spectrometry (ICP-OES), graphite furnace atomic absorption spectrometry (GFAAS) and As3+-Ce4+ catalytic spectrophotometry. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to select the elements into multi-element models, conditional logistic regression models were applied to analyze the association between elements and goiter risk. Bayesian kernel machine regression (BKMR) model was used to depict elements' mixtures and evaluate their joint effects. Finally, 7 elements were included in the multi-element model. We found that the concentrations of lithium (Li), strontium (Sr) and barium (Ba) had a negative effect with goiter risk, and lead (Pb) and iodine (I) showed an extreme positive effect. Additionally, compared with the lowest levels, patients with highest quartiles of I and Pb were 6.49 and 1.94 times more likely to have goiter, respectively. On the contrary, in its second and third quartiles, arsenic (As) showed a negative effect (both OR<1). BKMR model showed a certain interaction among Pb, As, Sr and Li on goiter risk. Further large sample studies are needed to confirm these findings in the future.

Thyroid hormones in relation to polybrominated diphenyl ether and metals exposure among rural adult residents along the Yangtze River, China.

Although several studies indicate that exposure to polybrominated diphenyl ethers (PBDEs) and metals may influence thyroid function, the evidence is limited and inconsistent in general population. The current study was conducted to determine the levels of plasma PBDEs and urinary metals and evaluate the associations of co-exposure to both with thyroid hormones (THs) among rural adult residents along the Yangtze River, China. A total of 329 subjects were included in current analyses, and 8 PBDEs congeners and 14 urinary metals were measured to reflect the levels of environmental exposure. Multiple linear regression models were used to evaluate the association between PBDEs, metals and THs levels. Bayesian Kernel Machine Regression (BKMR) was used to examine PBDEs and metals mixtures in relation to THs. The geometric mean (GM) and 95% confidence interval (CI) of total measured PBDEs was 65.10 (59.96, 70.68) ng/g lipid weights (lw). BDE-209 was the most abundant congener, with a GM (95% CI) of 47.91 (42.95, 53.26) ng/g lw, accounting for 73.6% of the total PBDEs. Free thyroxine (FT4) was significantly negatively associated with BDE-28, 47, 99, 100, 154, and 183, and urinary strontium [ß (95% CI): -0.04 (-0.07, -0.02)], but positively associated with selenium [ß (95% CI): 0.04 (0.02, 0.06)]. Free triiodothyronine (FT3) was negatively associated with BDE-28 [ß (95% CI): -0.03 (-0.05, -0.01)] and urinary arsenic [ß (95% CI): -0.01 (-0.02, -0.001)]. The current study did not observe a statistically significant association of thyroid-stimulating hormone (TSH) with PBDEs and urinary metals. BKMR analyses showed similar trends when these chemicals were taken into consideration simultaneously. We found no significant interaction in the association between individual chemical at the 25th versus 75th percentiles and THs estimates, comparing the results when other chemicals were set at their 10th, 50th, and 90th percentile levels. Further study is required to confirm these findings and determine potential mechanisms.

Exposure to 2,4-dichlorophenol, 2,4,6-trichlorophenol, pentachlorophenol and risk of thyroid cancer: a case-control study in China.

Thyroid cancer (TC) has inflicted huge threats to the health of mankind. Chlorophenols (CPs) were persistent organic pollutant and can lead to adverse effects in human health, especially in thyroid. However, epidemiological studies have revealed a rare and inconsistent relationship between internal exposure to CPs and TC risk. The purpose of this study was to investigate the correlation between urinary CPs and TC risk in Chinese population. From June 2017 to September 2019, a total of 297 histologically confirmed TC cases were recruited. Age- and gender-matched controls were enrolled at the same time. Gas chromatography-mass spectrometry (GC-MS) was used to determine the levels of three CPs in urine. Conditional logistic regression models were adopted to assess the potential association. Restricted cubic spline function was used to explore the non-liner association. After adjusting for confounding factors, multivariate analysis showed that, compared with the first quartile, the fourth quartile concentrations of 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP), and pentachlorophenol (PCP) were associated with TC risk (odds ratio (OR)2,4-DCP =2.28, 95% confidence interval (CI): 1.24-4.18; OR2,4,6-TCP =3.09, 95% CI: 1.66-5.77; ORPCP =3.30, 95% CI: 1.71-6.36, respectively), when CPs were included in the multivariate model and restricted cubic spline function as continuous variables, presenting significant dose-response relationships. Meanwhile, whether in the TC group with tumor diameter > 1 cm or metastatic TC, the changes of 2,4,6 TCP and PCP concentrations were positively correlated with the risk of TC. Our study suggests that higher concentrations of urinary CPs are associated with increased TC risks. Moreover, 2,4,6-TCP and PCP have certain effects on the invasiveness of thyroid cancer. Targeted public health policies should be formulated to reduce the CP pollution. These findings need further in-depth studies to confirm and relevant mechanism also needed to be clarified.

Multiple metal exposure and obesity: A prospective cohort study of adults living along the Yangtze River, China.

Association between long-term exposure to multiple metals and obesity remains inconclusive, and prospective evidence on the region along the Yangtze River was limited. Thus, our study aimed to examine the association of multiple metal exposure and obesity. We measured baseline urine levels of 22 metals of 982 adults living along the Yangtze River, incidence of obesity was calculated from body mass index (BMI) and waist circumference (WC) measured at follow-up survey. Cox proportional hazards models were used to examine the hazard ratios (HR) and 95% confidence interval (CI) for the association between urinary metals and obesity, and the mixing effect of metals on obesity was estimated by using quantile g-computation. In multiple-metal models, arsenic was significantly associated with BMI/obesity, with the HR in the highest quartiles of 0.33 (95% CI: 0.16, 0.69; p-trend = 0.004). The HRs for WC/obesity of arsenic and molybdenum were 0.49 (95% CI: 0.32, 0.75 for the fourth vs. first quartile; p-trend = 0.002) and 1.83 (95% CI: 1.25, 2.70; p-trend = 0.001), respectively. Quantile g-computation mixtures approach showed a significantly negative joint effect of multiple metals on WC/obesity, with the HR of 0.26 (95% CI: 0.14, 0.47; p < 0.001) when increasing all seventeen metals by one quartile. Our study suggests that all seventeen metal mixed exposure may be negatively associated with obesity. Further cohort studies are needed to confirm these findings and clarify the underlying biological mechanisms.

Social selection in cohort studies and later representation of childhood psychiatric diagnoses: The Danish National Birth Cohort.

Aim: This study aimed to estimate the relative representation of childhood psychiatric diagnoses and use of psychotropic medication in the Danish National Birth Cohort (DNBC) compared to the general population. Methods: The general population was identified as all childbirths in Denmark during 1998-2002 (N=344,160). Linking the DNBC (N=91,442) and the general population to the Danish national health registries, all children were followed until they received an ICD-10 psychiatric diagnosis, had a prescription of psychotropic medication or to the end of follow-up in 2013. The prevalence ratios (PRs) with corresponding 95% confidence intervals (CI) were estimated for each psychiatric diagnosis and by sex. Age at first diagnosis presented as means were compared using the one-sample t-test. Results: In the DNBC, the selected childhood psychiatric diagnoses were underrepresented by 3% (PR=0.97, 95% CI 0.94-0.99), ranging from a 20% underrepresentation for schizophrenia (PR=0.80, 95% CI 0.59-1.09) to a 6% over-representation for anxiety disorder or obsessive-compulsive disorder (PR=1.06, 95% CI 0.97-1.17). The majority of the specific diagnoses were modestly underrepresented in the DNBC compared to the general population, while use of psychotropic medication had similar representation. Girls were generally more underrepresented than boys. Depression was on average diagnosed 0.4 years earlier in the DNBC than in the general population (p=0.023). Conclusions: These findings suggest that the social selection may influence the prevalence of diagnosed childhood psychiatric disorders in the DNBC.

Preliminary investigation of the effects of an FCF inhibitor interference with Septin in the early stage embryos in mice.

The objective of the present study was to investigate the effects of for chlorfenuron (FCF) interference with the septin protein on early stage embryos in mice. The 1­cell embryos were collected and divided into an FCF interference group and a control group. The FCF interference group was cultured in FCF media and the control group was cultured in dimethyl sulphoxide media at 37˚C with 5% CO2 until the desired phase was achieved. Septin2 protein expression was detected using immunofluorescence and western blot analysis. Blastocyst α­tubulin was stained by immunofluorescence to observe the alterations in spindles and microtubules. The rate of early embryo development into blastocysts was significantly reduced following FCF treatment (P<0.05). In the control group, septin2 was observed with a confocal microscope; septin2 was expressed in embryos at all stages and mainly in the blastomeres from the 2­cell stage onwards, with the expression concentrated in the nuclei of the blastomeres as identified by strong fluorescence. In the FCF interference group, septin2 was weakly expressed in the nuclei of blastomeres at the 2­ and 4­cell stages, and in the granulated blastomeres at the 4­ and 8­cell stages. Expression was barely observed in and following the morula. Granulation was observed starting from the 4­ and 8­cell stages. Compared with the control group, the FCF interference group exhibited irregular microtubules, abnormal spindle morphology and disordered chromosome arrangement in the blastocysts. The septin2 protein was expressed throughout the early stage embryo from the 2­cell stage to the blastocyst and localized in the nuclei of blastomeres. When the septin protein experienced interference by the FCF inhibitor, septin2 protein expression was reduced, which simultaneously resulted in abnormal embryonic development, uneven cytoplasmic division, various sizes and a reduced number of blastomeres, granulation in the blastomeres, disordered blastocyst microtubule distribution, spindle shape alterations and an abnormality of chromosome arrangement.

[Effects of obesity on global genome DNA methylation and gene imprinting in mouse spermatozoa].

OBJECTIVE: To investigate the influence of high fat diet-induced obesity (HFDIO) on the differentially methylated region (DMR) of the imprinted gene and global genome methylation of sperm DNA. METHODS: We performed bisulfite sequencing on the DMR of the imprinted gene and global genome methylation of sperm DNA in the mouse model of HFDIO. RESULTS: No statistically significant differences were found between the HFDIO model and normal control mice in MEG3-IG (93.73 vs 97.26%, P = 0.252), H19 (98.00 vs 97.83%, P = 0.920), IGF2 (97.34 vs 96.25%, P =0.166), IGF2R (1.43 vs 1.11%, P = 0.695), PEG3 (0.19 vs 0.38%, P = 0.537), MEST (0.23 vs 0.68%, P = 0.315), NNAT (0.31 vs 0.00%, P = 0.134), or SNRPN (1.88 vs 3.13%, P = 0.628). A total of 8 942 DMRs were detected across the sperm genome (P <0.05). Gene functional enrichment analysis indicated that the enriched terms with the largest numbers of genes were the metabolic process (n = 1 482), RNA synthesis (n = 779), and transcription (n = 767). CONCLUSIONS: The methylation level underwent no significant change in the DMRs of the imprinted genes from the mice with HFDIO, but the CG methylation of the genes involved in the metabolic process, RNA synthesis and transcription were significantly altered.

Trim27 interacts with Slx2, is associated with meiotic processes during spermatogenesis.

ABSTARCT Formation of the XY body is believed to prevent recombination between X and Y chromosomes during meiosis. We recently demonstrated that SYCP3-like X-linked 2 (Slx2) could be involved in synaptonemal complex formation as well as XY body maintenance during meiosis. In order to further investigate the role and composition of XY body protein complexes in meiotic processes and spermatogenesis, a yeast 2-hybrid screening was performed, and the tripartite motif protein 27(Trim27) was found to interact with Slx2 and co-localized in the XY body. Trim27 has a tripartite motif (TRIM) consisting of a RING finger, B-box and coiled-coil domains, and is a transcriptional regulator that is expressed in various tumor cell lines. In this study, we showed that Slx2 and Trim27 were highly expressed in meiosis of mouse testis. And the Slx2/Trim27 interaction was confirmed in vivo by co-immunoprecipitation and mammalian 2-hybrid interaction assays. Moreover, cytoimmuno localization experiments revealed that Slx2/Trim27 was co-localized to the XY body of spermatocytes during meiosis, and immunohistochemical results revealed co-localization of Trim27 and γ-H2AX in the XY body of primary spermatocytes in the mouse testis. Trim27 may therefore be a transcriptional regulation protein connecting Slx2 and γ-H2AX, thereby promoting the formation of a more potent XY body protein complex in meiotic processes and spermatogenesis. In conclusion, Trim27 connecting Slx2 may regulate meiotic processes in multiple ways by influencing XY body formation and germ cell proliferation during spermatogenesis.

The risk of attention deficit hyperactivity disorder in children exposed to maternal smoking during pregnancy - a re-examination using a sibling design.

BACKGROUND: Conventional cohort studies have consistently shown that exposure to maternal smoking in pregnancy is associated with about twice the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. However, recent studies using alternative designs to disentangle the effect of social and genetic confounders have suggested that confounding may account for the association. In this study we aimed to estimate the association by a sibling design. METHODS: We used a design with half and full siblings in a Danish national register-based cohort on all singletons born between January 1991 and December 2006 and followed until January 2011. Data were available for 90% (N = 968,665) of the singleton live births in the period. We used the combination of the International Classification of Diseases (10th version) diagnosis of hyperkinetic disorder (HKD) and ADHD medication to identify children. We used sibling-matched (conditional) Cox regression to control social and genetic confounding. RESULTS: Using conventional cohort analyses, we found the expected association between pregnancy smoking and offspring ADHD (adjusted HR 2.01, 95% CI 1.94-2.07). In the sibling analysis, however, we did not detect such a strong association (adjusted HR 1.07, 95% CI 0.94-1.22). There was no difference between results for half- and full sibling analyses. The link between pregnancy smoking and low birth weight remained robust in the sibling design (adjusted OR 1.68, 95% CI 1.33-2.12). CONCLUSIONS: We found no support for prenatal smoking as a strong causal factor in ADHD. Our findings suggest that the strong association found in most previous epidemiological studies is likely to be due to a strong link between maternal smoking and maternal ADHD genetics or shared family environment. Pregnant women should still be encouraged to stop smoking because of other risks, but we have no reason to believe that this would reduce the risk of ADHD in the offspring.

Identification and Characterization of Xlr5c as a Novel Nuclear Localization Protein in Mouse Germ Cells.

BACKGROUND: Spermatogenesis is the complex process by which diploid stem cells generate haploid germ cells in gamete production. Members of the Xlr (X-chromosome linked, lymphocyte regulated) superfamily play essential roles in spermatogenesis. The expression, localization and role in spermatogenesis of one such member, Xlr5c, has not been reported previously. METHODOLOGY/PRINCIPAL FINDINGS: Xlr5c mRNA and protein levels in murine testes and other tissues were investigated using RT-PCR and Western blotting. Xlr5c was abundantly transcribed in mouse testes, particularly during the early stages of spermatogenesis and throughout prophase I in the nuclei of spermatocytes. Xlr5c was specifically localized at synaptonemal complexes(SCs) region in preleptotene and pachytene spermatocytes, as was the homologous Xlr protein Sycp3. CONCLUSIONS/SIGNIFICANCE: These results suggest that Xlr5c was abundantly transcribed in germ cells, localized at SCs region, where it may play a potential role during the early stages of spermatogenesis. Identification and characterization of this novel testis protein may offer a new perspective for understanding of the molecular mechanisms involved in germ cell differentiation.

Prenatal parental separation and body weight, including development of overweight and obesity later in childhood.

BACKGROUND: Early parental separation may be a stress factor causing a long-term alteration in the hypothalamic-pituitary-adrenal-axis activity possibly impacting on the susceptibility to develop overweight and obesity in offspring. We aimed to examine the body mass index (BMI) and the risk of overweight and obesity in children whose parents lived separately before the child was born. METHODS: A follow-up study was conducted using data from the Aarhus Birth Cohort in Denmark and included 2876 children with measurements of height and weight at 9-11-years-of-age, and self-reported information on parental cohabitation status at child birth and at 9-11-years-of-age. Quantile regression was used to estimate the difference in median BMI between children whose parents lived separately (n = 124) or together (n = 2752) before the birth. We used multiple logistic regression to calculate odds ratio (OR) for overweight and obesity, adjusted for gender, parity, breast feeding status, and maternal pre-pregnancy BMI, weight gain during pregnancy, age and educational level at child birth; with and without possible intermediate factors birth weight and maternal smoking during pregnancy. Due to a limited number of obese children, OR for obesity was adjusted for the a priori confounder maternal pre-pregnancy BMI only. RESULTS: The difference in median BMI was 0.54 kg/m2 (95% confidence intervals (CI): 0.10; 0.98) between children whose parents lived separately before birth and children whose parents lived together. The risk of overweight and obesity was statistically significantly increased in children whose parents lived separately before the birth of the child; OR 2.29 (95% CI: 1.18; 4.45) and OR 2.81 (95% CI: 1.05; 7.51), respectively. Additional, adjustment for possible intermediate factors did not substantially change the estimates. CONCLUSION: Parental separation before child birth was associated with higher BMI, and increased risk of overweight and obesity in 9-11-year-old children; this may suggest a fetal programming effect or unmeasured difference in psychosocial factors between separated and non-separated parents.

Parental smoking during pregnancy and ADHD in children: the Danish national birth cohort.

BACKGROUND: Prenatal maternal smoking has been associated with attention-deficit/hyperactivity disorder (ADHD) in children, but the causal nature of this association is still under scrutiny. We examined the association with maternal smoking and nicotine replacement use during pregnancy, using association with paternal smoking as a marker of potential genetic or social confounding. METHODS: We included 84 803 singletons who participated in the Danish National Birth Cohort. Information on parental smoking was reported by the mothers during pregnancy. Children with ADHD were identified from the Danish Psychiatric Central Register, the Danish National Patient Register, and the Register of Medicinal Product Statistics by the International Classification of Diseases, 10th Revision diagnosis or medication. We also used hyperactivity/inattention score of the parent-reported Strengths and Difficulties Questionnaire, included in the 7-year follow-up of the National Birth Cohort. RESULTS: Maternal and paternal smoking during pregnancy were associated with an elevated risk of ADHD defined by hospital diagnosis, medication, and hyperactivity/inattention score, but the association was stronger for maternal smoking than for paternal smoking. Compared with children born to nonsmoking mothers and smoking fathers, children born of smoking mothers and nonsmoking fathers had a higher risk of ADHD (adjusted hazard ratio = 1.26; 95% confidence interval, 1.03 to 1.53). We also saw a higher risk of ADHD in children of mothers who used nicotine replacement during pregnancy. CONCLUSIONS: Our findings indicate that the association between prenatal maternal smoking and ADHD may overestimate a causal link, but nicotine exposure or related factors may still play a causal role.

ILEI: a novel marker for epithelial-mesenchymal transition and poor prognosis in colorectal cancer.

AIMS: Accumulating evidence over the past decade has shown that abnormal activation of epithelial to mesenchymal transition (EMT) contributes to tumour progression and metastasis in colorectal cancer (CRC). In this study, we investigated the expression of interleukin-like EMT inducer (ILEI) and EMT-associated markers (E-cadherin, vimentin) in CRC tissues and determined the correlations between ILEI expression and clinicopathological characteristics, prognosis and EMT in CRC. METHODS AND RESULTS: In total, 194 patients diagnosed with CRC based on histopathological evaluation and those subjected to surgical resection at the First Hospital of China Medical University between 2003 and 2005 were examined. Immunohistochemical staining for ILEI, vimentin and E-cadherin was performed for each specimen. Cytoplasmic overexpression of ILEI usually accompanied down-regulation of E-cadherin and positive expression of vimentin. Conversely, ILEI was simultaneously down-regulated with overexpression of E-cadherin and negative expression of vimentin. ILEI overexpression was associated significantly with T-stage, N-stage, TNM stage and EMT phenotype (P = 0.024, <0.001, <0.001 and <0.001, respectively). Multivariate analysis revealed that ILEI expression was an independent prognostic factor for patient survival. CONCLUSIONS: Our findings indicate that cytoplasmic ILEI expression is a potential marker of EMT and tumour progression in CRC. ILEI is an independent predictive factor associated with poor prognosis in CRC.

Social conditions for people with Down syndrome: a register-based cohort study in Denmark.

Today, most persons with Down syndrome (DS) survive into middle age, but information on their social conditions as adults is limited. We addressed this knowledge gap using data from national registers in Denmark. We identified a national cohort of 1,998 persons with DS who were born between 1968 and 2007 (1,852 with standard trisomy 21, 80 with Robertsonian translocations and 66 with mosaicism) using the Danish Cytogenetic Register. We followed this cohort from 1980 to 2007. Information on social conditions (education, employment, source of income, marital status, etc.) was obtained by linkages to national registers, including the Integrated Database for Longitudinal Labor Market Research. For those aged 18 and older, more than 80% of persons with DS attended 10 years of primary school, with about 2% completing secondary or post-secondary education. About 4% obtained a full-time job, whereas the remaining mainly received public support from the government. Only a few (1-2%) of persons with DS were married or had a child. No significant differences in these social conditions were seen between males and females. More persons with mosaic DS attended secondary or post-secondary education, had a full-time job, were married, or had a child (18%, 28%, 15%, and 7%, respectively), compared with persons with standard DS (1%, 2%, 1%, and 1%, respectively). These data may provide families with better insight into social conditions and society with a better understanding of the social support needed for persons with DS.

Clinicopathological significance of claudin-4 in gastric carcinoma.

BACKGROUND: Aberrant expression of claudin proteins has been reported in a variety of cancers. Previous studies have demonstrated that overexpression of claudin may promote tumorigenesis and metastasis through increased invasion and survival of tumor cells. However, the prognostic significance of claudin-4 in gastric cancer remains unclear. METHODS: Immunohistochemistry was used to analyze the expression of claudin-4 in 329 clinical gastric cancer specimens and 44 normal stomach samples, 21 intestinal metaplasia samples, and 21 adjacent precursor lesions dysplasia samples. Statistical analysis methods were used to evaluate the relationship between claudin-4 expression and various clinicopathological parameters. Univariate and multivariate analyses were performed, respectively, to detect the independent predictors of survival. RESULTS: Claudin-4 expression was present in only 7(15.9%) normal gastric samples, but expression of claudin-4 in the intestinal metaplasia lesions and dysplasia lesions was 90.5% and 95.2%, respectively. The expression of claudin-4 was significantly associated with histological differentiation (P < 0.001) and tumor growth patterns (P < 0.001) but not associated with patient survival. However, intermediate type staining of claudin-4 exhibited a trend of correlation with patients' survival (P = 0.023). The five-year survival rate with low expression of claudin-4 in intermediate type (76.4%) was similar to expanding type (64.5%), while the high expression group (46.6%) was closer to infiltrative type (50.7%). CONCLUSIONS: The findings in this study demonstrate claudin-4 aberrant expression in gastric cancer and precursor lesions. The expression of claudin-4 could serve as a basis for identifying gastric cancer of the intermediate type.

The clinical significance of mesenchyme forkhead 1 (FoxC2) in gastric carcinoma.

AIMS: Mesenchyme forkhead 1 (FoxC2) is an epithelial-mesenchymal transition (EMT)-inducing factor. Previous studies have demonstrated that FoxC2 binds directly to the promoter region of p120-catenin (p120ctn). The aim of this study was to investigate the clinical significance of FoxC2 expression and the inter-relationship between FoxC2 and p120ctn, in gastric cancer. METHODS AND RESULTS: Immunohistochemistry was used to examine the expression of FoxC2 and p120ctn proteins in 325 gastric cancer samples. Staining for FoxC2 in cancer tissues was markedly stronger than in normal tissues. High FoxC2 expression was associated significantly with differentiation, invasion depth, lymph node metastasis and tumour stage. Patients with high FoxC2 expression or low p120ctn expression had a poor prognosis. In the high p120ctn expression group, the prognosis for patients with low FoxC2 expression was better than for the high FoxC2 group. Moreover, stepwise Cox regression showed that p120ctn was an independent prognostic factor, but FoxC2 in combination with p120ctn was not correlated significantly with survival. CONCLUSIONS: We found that FoxC2 and p120ctn play important roles in the progression and prognosis of gastric cancer. Moreover, FoxC2 and p120ctn should be evaluated further as novel biomarkers and therapeutic targets for gastric cancer treatment.

Prenatal maternal bereavement and congenital heart defects in offspring: a registry-based study.

OBJECTIVES: It has been suggested that maternal emotional stress during cardiogenesis may be a risk factor for congenital heart defects (CHD). We examined this association using bereavement around the time of conception as an indicator of maternal exposure to stress in a large registry-based study. METHODS: We identified 1,770,878 singletons born in Denmark from January 1, 1978, to December 31, 2008. Of these, 44,820 children were born to mothers who had lost a first-degree relative during the time period from 1 year before their last menstrual period until delivery (6080 mothers lost a child or partner, and 38,740 mothers lost a parent or sibling). CHD diagnoses were identified from the Danish Registry of Congenital Heart Disease. We used logistic regression models to calculate prevalence odds ratios (ORs) of CHD for exposed children compared with unexposed children. RESULTS: Exposed children had a slightly higher prevalence of CHD than unexposed children (0.94% vs 0.82%; adjusted OR = 1.11, 95% confidence interval 1.00-1.22). The association was most marked for children of mothers who had lost a child or partner (1.15% vs 0.82%; adjusted OR = 1.32, 1.04-1.67). CONCLUSIONS: Prenatal exposure to severe emotional stress may slightly increase the prevalence of CHD in offspring.

Cancer risks in parents who had a child with a congenital malformation.

Cancer risk in parents may be related to congenital malformations (CMs) in their children if they share genetic susceptibility or environmental exposure that may be teratogenic and carcinogenic. We conducted a population-based cohort study based on Danish register data. We identified 795,607 mothers and 781,424 fathers who had all their children between 1977 and 2007 in Denmark. Information on CM was obtained from the Danish Hospital Registry and information on cancer was obtained from the Danish Cancer Registry. Parents were followed from the birth of their first child until the diagnosis of cancer, death, emigration, or December 31, 2007. We used Cox regression models to estimate hazard ratios (HRs) for cancer including cancer in specific organs in mothers and fathers. Overall, 75,701 (9.5%) mothers and 72,724 (9.3%) fathers had at least one child diagnosed with CMs within the first year of life. Neither mothers (HR=1.04; 95% CI: 0.99-1.04) nor fathers (HR=1.03; 95% CI: 0.98-1.09) who had a child with a CM had a higher overall risk of cancer. Mothers (HR=0.76, 95% CI: 0.58-1.00) or fathers (HR=0.89, 95% CI: 0.66-1.19) who had a child with a chromosomal malformation had a lower overall cancer risk. The findings also showed a higher risk for some specific types of cancer in parents who had children with a CM in the specific system. Some, or perhaps all, of these findings may be due to chance caused by multiple comparisons. We present all results on paper or online to provide clues for further research and to avoid publication bias.