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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

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.

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. © 2013 Wiley Periodicals, Inc.

Aims Recent studies have revealed that glutamate decarboxylase 65 (GAD65) plays important roles in cancer progression. The role of GAD65 in gastric cancer development, progression and prognosis is currently unknown, and we aimed to investigate this. Methods and results Immunohistochemistry revealed that GAD65 expression in 313 gastric cancer tissues was significantly higher than in 60 adjacent non-tumour tissues. Moreover, the expression level of GAD65 significantly correlated with the depth of tumour invasion and TNM stage. GAD65 expression level was a significant prognostic factor in univariate survival analysis, but did not remain an independent prognostic factor following Cox multivariate analysis. For tumours with an intermediate type growth pattern, when those showing low expression of GAD65 were reclassified with expanding type tumours, and those showing high expression with infiltrative type tumours, there was a significant difference in prognosis between these two novel subgroups, and this remained a significant prognostic factor in multivariate analysis. Conclusions Our findings indicate that GAD65 is involved in the development and progression of gastric cancer as a tumour oncoprotein. Further elucidation of the molecular mechanisms underlying the role of GAD65 is warranted.

Objective To assess whether onset of rheumatoid arthritis (RA) prior to conception is associated with a delayed time to pregnancy (TTP). Methods The study included pregnant women from across Denmark who enrolled in the Danish National Birth Cohort between 1996 and 2002 and had planned or partly planned the cohort pregnancy. RA diagnosis was identified using the Danish National Hospital Discharge Registry. Self-reported data, including TTP, maternal age, parity, prepregnancy height and weight, maternal occupational status, smoking, and alcohol consumption, were collected using a detailed computer-assisted telephone interview at ∼16 weeks of gestation. We used logistic regression analyses as well as a complementary log regression model to examine whether TTP was influenced by RA, adjusting for the abovementioned variables. Results Overall, compared with women with no recorded RA (n = 74,255), women with prevalent RA (onset prior to conception) (n = 112) were slightly older (mean ± SD age 30.8 ± 4.3 years versus 29.7 ± 4.1 years), were more likely to have been treated for infertility (9.8% versus 7.6%), and were more likely to have taken >12 months to conceive (25.0% versus 15.6%). The association between RA and TTP was borderline significant after adjusting for covariates in the regression analyses (odds ratio 1.6 [95% confidence interval 1.0-2.4]). Similar results were obtained after restricting the analyses to women who had planned the pregnancy or those who were nulliparous before the cohort pregnancy. Conclusion Women with RA onset prior to conception had a slightly longer TTP compared with those who did not have RA, indicating a slight reduction in fecundity. Copyright © 2011 by the American College of Rheumatology.

Udgivelsesdato: 2009-Feb OBJECTIVES: To compare two post-abortion family planning (FP) service packages on contraceptive use and repeat abortion rate among young women in three cities in China. METHODS: In this cluster-randomized trial, one FP service package included provision of limited information and referral to existing FP services, and the other, more comprehensive, package consisted--in addition to the above simple package--of individual counselling, free provision of contraceptive materials, and involvement of the male partner. Eight matched pairs of hospitals were certified by centralized randomization. Women undergoing abortion were followed up for six months, and data were collected in two rounds, before and after the intervention. RESULTS: We followed a total of 2336 women younger than 25 years (555 before and 555 after the simple intervention package; 634 before and 592 after the comprehensive intervention package). Both packages increased use of any contraceptive method, but the comprehensive approach also increased use of more effective methods. Odds ratios for consistent and correct use of condoms were 2.32 (95% confidence interval 1.55-3.46) and 2.78 (1.81-4.26), respectively, compared with the simple package. The rates of unwanted pregnancies and repeat abortions were somewhat reduced for both packages, with no significant statistical difference between them. CONCLUSION: Couples who received the comprehensive post-abortion FP service appear to use more effective contraceptive methods and show better compliance.

Objective To examine the timing of reaching developmental milestones in children born post-term. Design Cohort study. Setting The Danish National Birth Cohort: children born between 1997 and 2003. Population Data were obtained from a cohort of 92 892 pregnancies participating in the first pregnancy interview. All singletons born in gestational weeks 39–45 were identified. The study was then restricted to children who participated in an interview at the age of approximately 18 months and had information on at least one developmental milestone. We excluded children of mothers with chronic diseases from the final analysis. The remaining study population constituted of 43 915 singletons (27 503 born at term; 16 412 born post-term). Methods Logistic regression was used to calculate odds ratios of late achievement of these developmental milestones, adjusted for potential confounding factors. Main outcome measures Achieving developmental milestones at the time of interview or at a certain age. Results More children born post-term achieved the assessed developmental milestones compared with children born at term (39–40 weeks). A test for trend for gestational ages 39, 40, and 41 weeks also showed a positive trend at achieving developmental milestones with gestational age at birth in nine out of 14 milestone items. Conclusions Children born post-term appear to reach the main developmental milestones at an earlier age than children born at term. The association could also result from bias related to a longer time between conception and interviewing, misclassification of end points, or selection bias.

Udgivelsesdato: 2006-Apr OBJECTIVE: We conducted a follow-up study to examine whether exposure to pesticides during pregnancy had an adverse effect on pregnancy outcomes among Danish gardeners and farmers. METHODS: Using data from the National Birth Cohort in Denmark, we identified 226 pregnancies of gardeners and 214 pregnancies of farmers during 1997 through 2003. Work activities and exposure to pesticides were reported in an interview (around 16 weeks of gestation). Totally, 62,164 other workers in the cohort served as a reference group. Pregnancy outcomes were obtained by linkage to the national registers. Cox regression was applied to analyze late fetal loss and congenital malformations, and logistic regression was used to analyze preterm birth and small for gestational age. RESULTS: There were no significant differences in the studied pregnancy outcomes between gardeners or farmers and all other workers, except for an increased risk of very preterm birth for gardeners and a favorable birth weight for farmers. With the exception of biologic approach used in gardening, neither work activities nor exposure to pesticides showed a significant increased risk of adverse birth outcomes among gardeners or farmers. CONCLUSIONS: Our data suggest little effect of occupational exposures to pesticides on pregnancy outcomes among gardeners or farmers in Denmark. The results may not apply to other countries.

Fatal occupational injuries in a new development region in Shanghai in east China are described. All occupational deaths in the East Pujiang New Area during the period 1991 through 1997 were abstracted from multiple, overlapping source documents. There were 426 deaths and a crude mortality rate of 9.1 per 100,000 workers. The death rate was highest in 1995 (14.6%), when expansion in the area was most rapid. The construction sector accounted for 55% of the deaths, followed by manufacturing (23%) and transport, storage, and telecommunications (11%). Falls, collisions, struck by/against incidents, and electrocutions accounted for 80% of all deaths. Falls led all other causes of deaths (33%) and were particularly prevalent in the construction industry (46% of all deaths in construction). The development of ongoing, comprehensive injury surveillance systems in the People's Republic of China will be essential to target and evaluate injury prevention activities in the future.

Two hundred thirty-five work-related deaths occurred in the construction industry in a new economic development area in eastern China between 1991 and 1997. These fatalities represented 55% of all occupational deaths. The average annual mortality rate was 51.5 per 100,000 construction workers. Falls were the leading cause of death (46.4%). Falls, collisions, struck by/against something, electrocutions, and excavation cave-ins were the main fatality antecedents, accounting for nearly 93.6% of all fatalities. The most common antecedents for incidents with multiple fatalities were falls, crane-related events, poisoning, and fire. These categories of antecedents were similar to those encountered in the construction industry in the United States. These data suggest that organizations need to focus on these event types when planning their prevention activities. Moreover, improved surveillance systems including computerized databases with narrative descriptions of injury events, antecedent factors, and person-time at-risk data are needed to target interventions more precisely.

The authors carried out a descriptive analysis of acute chemical intoxication in a large petrochemical corporation with 38,000 employees, located in a suburban district of Shanghai, China, to determine the chemicals involved and the primary causes of the incidents. Between 1977 and 1997, 350 cases of acute chemical-intoxication were recorded, resulting in a total of 541 workers with symptoms. Of these, 483 were male and 58, female, with over half the victims under 30 years old. Two hundred and seventy-five cases were serious enough to necessitate hospital admission. There were 266 cases of chemical irritation or inhalation responses (49.2%), 215 cases of mild chemical poisoning (39.7%), 31 cases of moderate poisoning (5.7%), and 29 cases resulting in critical injury (5.4%), including eight deaths (1.5%). The main causes of injury reported by patients were lack of training about safety (63%) and equipment failure (23%). The chemicals involved were asphyxiating gases (302 cases; 55.8%), irritating gases (111 cases; 20.5%), and other toxins. Intervention strategies for the prevention of acute chemical exposures were suggested to the corporation.

To explore the possible oxidative stress induced by lead, heparinized whole blood and urine of 66 secondary smelter lead workers (46 for Comet assay) and 28 controls were collected. The concentrations of blood lead (BPb) and urinary lead (UPb) and alpha-aminolevulinic acid (alpha-ALA), indices of lead exposure level of the body, were determined. Malondialdehyde (MDA) concentrations and superoxide dismutase (SOD) activity of plasma were also measured. Single-cell gel (SCG, Comet assay) was used to measure the DNA damage of peripheral blood cells. There was a positive correlation between the presence of Pb in blood and significant increases in MDA levels and SOD activity. Alcohol consumption and smoking with increased exposure to Pb was associated with enhanced DNA damage. A positive correlation was found between MDA and DNA damage.

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.

Several studies have shown substantially longer survival among persons with Down syndrome in recent decades. We examined survival patterns among Danish persons with Down syndrome by karyotype. A national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population were followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% confidence interval 3.51–7.08), 8.94 (8.32–9.60), and 10.23 (7.50–13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects. Recent birth cohorts of persons with Down syndrome experienced declining mortality, likely due to treatment for congenital heart defects, and persons with mosaic trisomy 21 had better survival than persons with other Down syndrome karyotypes. Genet Med 2013:15(1):64–69

To investigate the role of immunity-related medical conditions in the etiology of pancreatic cancer, we analyzed data from a population-based case-control study of pancreatic cancer conducted in Shanghai during 1992 and 1993. Information on prior histories of selected auto-immune diseases and allergic conditions was obtained from 108 incident pancreatic-cancer cases and 275 age- and gender-frequency matched controls by face-to-face interviews using a structured questionnaire. A prior history of auto-immune diseases was associated with a 2-fold elevated risk of pancreatic cancer (95% CI = 1.0-4.2), with an indication of a dose-response relation for the number of reported diseases. In contrast, a prior history of allergic condition was related to reduced risk (OR = 0.6, 95% CI = 0.4-1.1). With the possible exception of drug allergy, such an inverse association was seen for virtually all allergic conditions., although none of the OR was statistically significant. This study suggests that host immune function may be involved in the etiology of pancreatic cancer. Further investigations into the mechanism of these observed associations are warranted.

Objective At present, only the number of metastatic lymph nodes (LNs+) is used for the pN category of AJCC TNM system for colon cancer. Recently, the ratio of metastatic to examined lymph nodes (LNR) has been reported to represent powerful independent predictive capacity in colon cancer. We sought to propose a novel category (nLN) which intergrades LNR and LNs+ into the AJCC staging system for colon cancer. Design 34476 patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) dataset with stage III colon cancer were reviewed. Harrell's C statistic was used to evaluate the predictive capacity. The Cox proportional hazards model was used to construct a novel category. Results The LNR category had more predictive capacity than the pN category in whole groups of patients (Harrell's C index: 0.6194 vs 0.6113, p = 0.003). Subgroup analysis showed that the LNR category was not better than pN category in predictive capacity if the number of lymph nodes examined was more than 13. We also found that there was significant survival heterogeneity among different pN categories at the same LNR category (P

BackgroundHuman heparanase plays an important role in cancer development and single nucleotide polymorphisms (SNPs) in the heparanase gene (HPSE) have been shown to be correlated with gastric cancer. The present study examined the associations between individual SNPs or haplotypes in HPSE and susceptibility, clinicopathological parameters and prognosis of gastric cancer in a large sample of the Han population in northern China.Methodology/principal findingsGenomic DNA was extracted from formalin-fixed, paraffin-embedded normal gastric tissue samples from 404 patients and from blood from 404 healthy controls. Six SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A chi-square (χ2) test and unconditional logistic regression were used to analyze the risk of gastric cancer; a Log-rank test and Cox proportional hazards model were used to produce survival analysis and a Kaplan-Meier method was used to map survival curves. The mean genotyping success rates were more than 99% in both groups. Haplotype CA in the block composed of rs11099592 and rs4693608 had a greater distribution in the group of Borrmann types 3 and 4 (P = 0.037), the group of a greater number of lymph node metastases (N3 vs N0 group, P = 0.046), and moreover was correlated to poor survival (CG vs CA: HR = 0.645, 95%CI: 0.421-0.989, P = 0.044). In addition, genotypes rs4693608 AA and rs4364254 TT were associated with poor survival (P = 0.030, HR = 1.527, 95%CI: 1.042-2.238 for rs4693608 AA; P = 0.013, HR = 1.546, 95%CI: 1.096-2.181 for rs4364254 TT). There were no correlations between individual SNPs or haplotypes and gastric cancer risk.Conclusions/significanceA functional haplotype in HPSE was found, which included the important SNP rs4693608. SNPs in HPSE play an important role in gastric cancer progression and survival, and perhaps may be a molecular marker for prognosis and treatment values.

Aims: To explore the relation between employment status, type of unemployment and pregnancy outcomes. Methods: A cohort study of 7,282 pregnancies of unemployed women and 56,014 pregnancies among women in paid jobs was performed within the Danish National Birth Cohort. Pregnancy outcomes were ascertained and information about lifestyle, occupational, medical, and obstetric factors was obtained. Logistic regression was used to calculate odds ratios (OR) for fetal loss, congenital anomalies, multiple births, sex ratio, preterm and very preterm birth and small for gestational age status, adjusting for lifestyle, medical and obstetric factors. Results: There were no differences in pregnancy outcomes between employed and unemployed women but women receiving unemployment benefit had an increased risk of preterm birth (adjusted OR (aOR) 1.16, 95% confidence interval (95% CI) 1.03—1.31) and having a small for gestational age child (aOR 1.08, 95% CI 1.00—1.19) compared with employed women. Women receiving sickness or maternity benefit had an increased risk of multiple birth (aOR 1.70, 95% CI 1.43—2.04), preterm (aOR 1.47, 95% CI 1.22—1.77) and very preterm birth (aOR 1.88, 95% CI 1.22—2.89), while those receiving an unreported type of support had an increased risk of preterm birth (aOR 1.40, 95% CI 1.02—1.93). Conclusions: We found no indication that being unemployed during pregnancy benefits or endangers the health of the child. Within the subgroups of unemployed women, we observed that women receiving unemployment and sickness or maternity benefits were at higher risk for some adverse pregnancy outcomes. © 2011, the Nordic Societies of Public Health. All rights reserved.

Udgivelsesdato: 2010-Feb-6 BACKGROUND It has previously been reported that children born after infertility treatment had a slight delay in early motor milestones. In this study, we examined whether children of infertile couples with or without infertility treatment had a higher risk of developmental coordination disorder (DCD). METHODS We used data on parental infertility and DCD among 23 167 singletons from the Danish National Birth Cohort (1996-2002). Data on time to pregnancy (TTP) and infertility treatment were collected early in pregnancy. Data on DCD in children were collected using the Developmental Coordination Disorder Questionnaire, filled in by the mothers during follow-up when the children were 7 years old. We used the recommended cut-off for the age group to classify children. RESULTS Compared with children born of fertile couples, children conceived after a waiting TTP of longer than 12 months had a slightly higher risk of DCD [odds ratio (OR) 1.35, 95% confidence interval (CI) 1.03-1.77], but the estimated OR was not significant in children born after infertility treatment (OR 1.19, 95% CI 0.86-1.66). None of the individual treatment procedures was significantly associated with a higher risk of DCD. Children of parents who had not planned their pregnancy showed no elevated risk. CONCLUSIONS Our findings are overall reassuring, although it is possible that low fecundity may be associated with a modestly increased risk of DCD.

Udgivelsesdato: 2009-Mar Babies born of infertile couples, regardless of treatment, have a higher risk of preterm birth and low birthweight, conditions associated with delayed development. We examined developmental milestones in singletons as a function of parental infertility [time to pregnancy (TTP) > 12 months] and infertility treatment. From the Danish National Birth Cohort (1997-2003), we identified 37 897 singletons born of fertile couples (TTP < or = 12 months), 4351 born of infertile couples conceiving naturally (TTP > 12 months), and 3309 born after infertility treatment. When the children were about 18 months old, mothers reported 12 developmental milestones by responding to structured questions. We defined a failure to achieve the assessed milestone or the minimal numbers of milestones in a summary (motor, or cognitive/language skills) as delay. Naturally conceived children born of infertile couples had a pattern of psychomotor development similar to that of children born of fertile couples, but increasing TTP correlated with a modest delay. When the analysis was restricted to infertile couples (treated and untreated), children born after treatment showed a slight delay in cognitive/language development (odds ratio 1.24, [95% confidence interval 1.01, 1.53]) for not meeting at least three out of six cognitive/language milestones); children born after intracytoplasmic sperm injection (ICSI) had the highest estimated relative risk of delay for most milestones, especially motor milestones. These results suggest that a long TTP may be associated with a modest developmental delay. Infertility treatment, especially ICSI, may be associated with a slight delay for some of these early milestones.

Udgivelsesdato: null-null In hospitals, women of reproductive age do a range of work tasks, some of which are known to carry potential risks. Tasks such as working with radiation, chemicals, and infectious agents, as well as performing heavy lifting or tasks requiring erratic sleep patterns have been reported to increase the risk of reproductive failures. Our aim was to study pregnancy outcomes in female hospital workers in Denmark. We performed a cohort study of 5976 female hospital workers and used as a reference group 60,890 women employed outside of hospitals. The reproductive health of hospital workers working during pregnancy is comparable to those of non-hospital workers for the majority of reproductive failures studied. However, an increased prevalence of congenital abnormalities was noted in some subgroups of hospital workers, which may indicate that some hospital work still entails fetotoxic hazards.

Udgivelsesdato: 2008 BACKGROUND: Since paternal age correlates with some diseases that have a high case-fatality, a paternal age effect on offspring's survival is expected but unsettled. We examined the association between paternal age and mortality in children in a large population-based cohort taking maternal age and socioeconomic factors into account. METHODS: From the Danish Fertility Database (1980-1996), we identified 102,879 couples and their firstborn singleton children. Information on childhood death (N = 831) was obtained by linking the cohort to the nationwide register on cause of death (1980-1998). RESULTS: We observed a U-shaped association between paternal age and the overall mortality rate in children up to 18 years of age. Adjustment for maternal age and other confounders reduced the mortality rate ratio (MRR) for children of younger fathers but not for children of older fathers. Compared with children of fathers aged between 25 and 29 years, the adjusted MRR was 1.77 (95% confidence interval 1.28-2.45) for children of fathers aged between 45 and 49 years and 1.59 (1.03-2.46) for children of fathers aged 50 years or more. The cause-specific MRRs were highest for congenital malformations [2.35 (1.42-3.88)] and injury or poisoning [3.43 (1.49-7.92)] for children of fathers aged 45 years or more. CONCLUSION: Our data revealed a higher mortality in offspring of fathers aged 45 years or more that lasted into adulthood. This adds to the cumulating evidence on adverse effects of advanced paternal age in procreation.

BACKGROUND: We have previously observed that an increasing time to pregnancy (TTP) is associated with a reduced frequency of twin deliveries in couples not receiving infertility treatment. By using updated information, we assessed the frequencies of dizygotic (DZ) and monozygotic (MZ) twin deliveries as a function of infertility (TTP > 12 months), as well as infertility treatment. METHODS: From the Danish National Birth Cohort (1997-2003), we identified 51 730 fertile couples with TTP 12 months and 5163 infertile couples who conceived after treatment. Information on zygosity, available for part of the cohort (1997-2000), was based on standardized questions on the similarities between the twins at the age of 3-5 years. RESULTS: Compared with fertile couples, the frequency of DZ twin deliveries was lower for infertile couples conceiving naturally (odds ratio 0.4, 95% confidence interval 0.2-0.7) and was much higher for infertile couples conceiving after treatment (17.3, 14.4-20.7). The frequency of DZ twin deliveries decreased with TTP in untreated couples, whereas the frequency of MZ twin deliveries remained constant. CONCLUSIONS: The frequency of DZ twin deliveries decreased with TTP and substantially increased with infertility treatment, whereas MZ twin deliveries remained substantially unchanged. Udgivelsesdato: 2007-Apr

Udgivelsesdato: 2006-Jan AIMS: To examine pregnancy outcomes in women doing laboratory work. METHODS: Using data from the Danish National Birth Cohort (1997-2003), the authors conducted a prospective cohort study of 1025 female laboratory technicians and 8037 female teachers (as reference). The laboratory technicians were asked about laboratory work tasks during pregnancy in an interview (at around 16 weeks of gestation). Pregnancy outcomes were obtained by linking the cohort to the national registers. Hazard ratios (HRs) of late fetal loss and diagnosing of congenital malformations were calculated by using Cox regression, and odds ratios (ORs) of preterm birth and small for gestational age were calculated by using logistic regression. RESULTS: Overall, there were no significant differences in pregnancy outcomes between laboratory technicians and teachers. However, we found that laboratory technicians working with radioimmunoassay or radiolabelling had an increased risk of preterm birth (OR = 2.2, 95% CI 0.8 to 6.2 for radioimmunoassay, and OR = 1.9, 95% CI 0.8 to 4.6 for radiolabelling) and "major" malformations (HR = 2.1, 95% CI 1.0 to 4.7 for radioimmunoassay, and HR = 1.8, 95% CI 0.9 to 3.7 for radiolabelling). The ORs of preterm birth doubled for women working with these tasks every day or several times a week. When an exposure matrix was applied, an increased risk of "major" malformations for exposure to organic solvents was seen. CONCLUSIONS: The results did not indicate any high risk of reproductive failures in laboratory technicians in general. Exposure to radioisotopes may carry a high risk of preterm birth and congenital malformations. This finding deserves further investigation.

BACKGROUND: Spontaneous mutations in germ cells increase with male age, but an association between paternal age and congenital malformations is not well established. We conducted a population-based cohort study to estimate this association. METHODS: A study population of couples and their firstborn children were identified in the Danish Fertility Database between 1980 and 1996 (n = 71937). Diagnoses of congenital malformations in children were obtained by linkage to the nationwide hospital register (1980–1999). RESULTS: Overall, there were no differences in the prevalence of malformations as a function of paternal age. However, the prevalence of malformations of extremities and syndromes of multiple systems, as well as Down’s syndrome, increased with increasing paternal age. For example, in comparison with fathers age 20–29 years, adjusted hazard ratio of syndromes of multiple systems was 1.15 [95% confidence interval (CI) 0.81–1.65] for age 35–39 years, 1.33 (95% CI 0.79–2.25) for age 40–44 years, 1.73 (95% CI 0.82–3.65) for age 45–49 years, and 3.20 (95% CI 1.37–7.48) for age 50 years (test for trend P = 0.01). CONCLUSIONS: Our data suggest that advanced paternal age may be associated with an excess occurrence of some specific malformations. The association could be caused by mutations of th e gametes in men induced by biological or environmental factors.

Background: There is growing evidence that advanced paternal age can be a reproductive hazard. Methods: We studied couples and their first children using nationwide registers in Denmark between 1980 and 1996. We restricted the analysis to mother's age 20-29 years. We estimated odds ratios (ORs) of preterm (

Objective: The Danish National Birth Cohort (DNBC) was used to examine whether shift work or job stress correlate with late fetal loss. Methods: We identified 33,694 pregnancies of daytime workers and 8,075 pregnancies of shift workers in women recruited to the DNBC between 1998 and 2001. Pregnancy outcomes were obtained by linkages to the national registers. Hazard ratios of fetal loss were calculated by using Cox regressions with left truncation. Results: Fixed night work was associated with fetal loss (hazard ratio = 1.85, 95% confidence interval = 1.00-3.42). No high risk of fetal loss was seen for other types of shift work. Job stress, as measured in our study, was not associated with fetal loss. Conclusions: Our results suggest that fixed night work during pregnancy increases the risk of late fetal loss.

Background: New evidence suggests that advanced paternal age is a reproductive hazard, but we do not know whether paternal age affects the physical conditions of newborn infants as measured by the Apgar score. Methods: We conducted a register-based cohort study of 70,347 couples and their first singleton infants by using data from the Danish Fertility Database (1980–1996). Information on Apgar score was obtained by linking the children to the National Birth Register. Results: The odds ratio for having a baby with a 1-minute Apgar score of 1–3 was 1.64 (95% confidence interval = 1.08–2.48) for fathers 45 to 49 years of age and 1.49 (0.76–2.94) for fathers 50+ years compared with fathers 20 to 29 years (P for trend = 0.011). The risk of having a 5-minute Apgar score less than 7 increased among fathers 45+ years old (P for trend = 0.178). Conclusions: Our data suggest a modest effect of advanced paternal age on the Apgar score.

Background The single nucleotide polymorphisms (SNPs) in matrix metalloproteinase 1(MMP-1)play important roles in some cancers. This study examined the associations between individual SNPs or haplotypes in MMP-1 and susceptibility, clinicopathological parameters and prognosis of gastric cancer in a large sample of the Han population in northern China. Methods In this case–controlled study, there were 404 patients with gastric cancer and 404 healthy controls. Seven SNPs were genotyped using the MALDI-TOF MS system. Then, SPSS software, Haploview 4.2 software, Haplo.states software and THEsias software were used to estimate the association between individual SNPs or haplotypes of MMP-1 and gastric cancer susceptibility, progression and prognosis. Results Among seven SNPs, there were no individual SNPs correlated to gastric cancer risk. Moreover, only the rs470206 genotype had a correlation with histologic grades, and the patients with GA/AA had well cell differentiation compared to the patients with genotype GG (OR=0.573; 95%CI: 0.353–0.929; P=0.023). Then, we constructed a four-marker haplotype block that contained 4 common haplotypes: TCCG, GCCG, TTCG and TTTA. However, all four common haplotypes had no correlation with gastric cancer risk and we did not find any relationship between these haplotypes and clinicopathological parameters in gastric cancer. Furthermore, neither individual SNPs nor haplotypes had an association with the survival of patients with gastric cancer. Conclusions This study evaluated polymorphisms of the MMP-1 gene in gastric cancer with a MALDI-TOF MS method in a large northern Chinese case-controlled cohort. Our results indicated that these seven SNPs of MMP-1 might not be useful as significant markers to predict gastric cancer susceptibility, progression or prognosis, at least in the Han population in northern China.

OBJECTIVES: The Danish National Birth Cohort (DNBC) was used to examinepregnancy outcomes among female hairdressers and neurodevelopment in theiroffspring. METHODS: A population-based cohort study was conducted of 550hairdressers and 3216 shop assistants (reference group) by using data from theDanish National Birth Cohort between 1997 and 2003. Information on jobcharacteristics was reported by the women in the first interview (around 17weeks of gestation). Pregnancy outcomes were obtained by linkage to the nationalregisters. Developmental milestones were reported by the mother at the fourthinterview, when the child was approximately 19 months old. Cox regression wasapplied to analyze fetal loss and congenital malformation. Logistic regressionwas used to analyze other pregnancy outcomes and developmental milestones.RESULTS: We found no significant differences in fetal loss, multiple births,gender ratio, preterm birth, small-for-gestational age, congenitalmalformations, or achievement of developmental milestones among the children ofhairdressers and shop assistants. CONCLUSIONS: The results do not indicate thatchildren of hairdressers in Denmark currently have a high risk of fetalimpairment or delayed psychomotor development.

OBJECTIVE: To examine the association between infertility, with or without treatment, and fetal growth, as well as perinatal and infant mortality. METHODS: From the Danish National Birth Cohort (1997-2003), we identified 51,041 singletons born of fertile couples (time to pregnancy 12 months or less), 5,787 born of infertile couples conceiving naturally (time to pregnancy more than 12 months), and 4,317 born after treatment. We defined small for gestational age (SGA) as the lowest 5% of birth weight by sex and gestational age. RESULTS: Crude estimates suggested an increased risk of perinatal mortality and SGA among infertile couples (treated and untreated), but the odds ratios (ORs) of perinatal mortality among infertile couples were attenuated after adjustment for maternal age and body mass index (1.32, 95% confidence interval [CI] 0.95-1.84 among untreated and 1.26, 95% CI 0.86-1.85 among treated couples). The elevated risk of SGA among infertile couples persisted after adjustment for maternal age, parity, and smoking (OR 1.24, 95% CI 1.10-1.40 among untreated, and OR 1.40, 95% CI 1.23-1.60 among treated). The risk of SGA increased with time to pregnancy, and a longer time to pregnancy was associated with a small reduction in birth weight across the whole distribution. CONCLUSION: The increased risk of SGA observed among infertile couples with or without infertility treatment suggests that infertility may be a risk factor for intrauterine growth restriction. Treatment per se may have little effect on fetal growth. A small-to-moderate increased risk of perinatal mortality in infertile couples cannot be ruled out due to the small number of cases. LEVEL OF EVIDENCE: II. Udgivelsesdato: 2007-Dec

Udgivelsesdato: 2005-Apr OBJECTIVES: The Danish National Birth Cohort was used to examine whether laboratory work was associated with reduced fecundity. METHODS: Self-reported data on laboratory work and waiting time to pregnancy (0-2, 3-5, 6-12 and > 12 months) were used for 829 female laboratory technicians interviewed in 1997-2003. Altogether 6250 female teachers formed the reference group. A discrete-time survival analysis with a complementary log-log link was applied to estimate the fecundability ratio between the exposed and unexposed women, with adjustment for maternal age, gravidity, smoking, prepregnancy body mass index, and paternal job. RESULTS: No difference in time to pregnancy was found between the laboratory technicians and teachers or between the laboratory technicians with different exposures. The adjusted fecundability ratio for the laboratory technicians was 0.94 [95% confidence interval (95% CI) 0.86-1.02] for all pregnancies and 0.98 (95% CI 0.86-1.13) for first pregnancies. A healthy worker effect was found for the laboratory technicians working with the work processes under study. CONCLUSIONS: The results do not suggest that laboratory work in Denmark at present impairs female fecundity.

To investigate whether parents of children with congenital malformations more often developed cancer after birth of the child, a population-based case-control study in Denmark was undertaken. By linking the Cancer Registry with the Central Population Registry, we identified 8783 cancer patients having their first child born between 1977 and 1995 before the cancer was diagnosed. Parents of 41 206 firstborn children of a 10% random sample of newborns from the Birth Registry between 1980 and 1995 were identified as controls. We obtained malformation diagnoses of children of cases and controls by linking to the Hospital Discharge Registry. We estimated the association between malformation and cancer by using logistic regression, adjusting for maternal age at birth and sex of child. We found no increased risk of cancer in parents having children with malformations in general, but a higher cancer risk in parents of children born with cleft lip/palate, odds ratio (OR) for all cancer=1.8 (95% confidence interval 1.0–3.2), OR for lymphomas=4.2 (1.3–13.5) and OR for leukaemia=8.1 (2.0–33.7). This association was not restricted to cancer cases diagnosed shortly after birth of the child. Our results suggest a common genetic association between these diseases, but further studies are needed. British Journal of Cancer (2002) 87, 524–528. doi:10.1038/sj.bjc.6600488 www.bjcancer.com © 2002 Cancer Research UK

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 P 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.