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1.  Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark 
British Journal of Cancer  2002;87(5):524-528.
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
doi:10.1038/sj.bjc.6600488
PMCID: PMC2376161  PMID: 12189550
cancer; congenital malformation; cleft lip and palate; case-control study; record linkage
2.  Direct evidence of milk consumption from ancient human dental calculus 
Scientific Reports  2014;4:7104.
Milk is a major food of global economic importance, and its consumption is regarded as a classic example of gene-culture evolution. Humans have exploited animal milk as a food resource for at least 8500 years, but the origins, spread, and scale of dairying remain poorly understood. Indirect lines of evidence, such as lipid isotopic ratios of pottery residues, faunal mortality profiles, and lactase persistence allele frequencies, provide a partial picture of this process; however, in order to understand how, where, and when humans consumed milk products, it is necessary to link evidence of consumption directly to individuals and their dairy livestock. Here we report the first direct evidence of milk consumption, the whey protein β-lactoglobulin (BLG), preserved in human dental calculus from the Bronze Age (ca. 3000 BCE) to the present day. Using protein tandem mass spectrometry, we demonstrate that BLG is a species-specific biomarker of dairy consumption, and we identify individuals consuming cattle, sheep, and goat milk products in the archaeological record. We then apply this method to human dental calculus from Greenland's medieval Norse colonies, and report a decline of this biomarker leading up to the abandonment of the Norse Greenland colonies in the 15th century CE.
doi:10.1038/srep07104
PMCID: PMC4245811  PMID: 25429530
3.  RNF4 is required for DNA double-strand break repair in vivo 
Cell Death and Differentiation  2012;20(3):490-502.
Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiation-induced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.
doi:10.1038/cdd.2012.145
PMCID: PMC3569989  PMID: 23197296
DNA damage; homologous recombination; RNF4; BRCA1; MDC1; Rad51; spermatogenesis
4.  Antenatal maternal bereavement and childhood cancer in the offspring: a population-based cohort study in 6 million children 
British Journal of Cancer  2012;107(3):544-548.
Background:
Prenatal stress may increase the susceptibility to childhood cancer by affecting immune responses and hormonal balance. We examined whether antenatal stress following maternal bereavement increased the risk of childhood cancer.
Methods:
All children born in Denmark from 1968 to 2007 (N=2 743 560) and in Sweden from 1973 to 2006 (N=3 400 212) were included in this study. We compared cancer risks in children born to women who lost a first-degree relative (a child, spouse, a parent, or a sibling) the year before pregnancy or during pregnancy with cancer risks in children of women who did not experience such bereavement.
Results:
A total of 9795 childhood cancer cases were observed during follow-up of 68 360 707 person years. Children born to women who lost a child or a spouse, but not those who lost other relatives, had an average 30% increased risk of any cancer (hazard ratio (HR) 1.30, 95% confidence interval (CI) 0.96–1.77). The HRs were the highest for non-Hodgkin disease (512 cases in total, HR 3.40, 95% CI 1.51–7.65), hepatic cancer (125 cases in total, HR 5.51, 95% CI 1.34–22.64), and testicular cancer (86 cases in total, HR 8.52, 95% CI 2.03–37.73).
Conclusion:
Our data suggest that severe antenatal stress following maternal bereavement, especially due to loss of a child or a spouse, is associated with an increased risk of certain childhood cancers in the offspring, such as hepatic cancer and non-Hodgkin disease, but not with childhood cancer in general.
doi:10.1038/bjc.2012.288
PMCID: PMC3405225  PMID: 22759879
childhood cancer; bereavement; prenatal stress; mother; association
5.  Familial risks in nervous system tumours: joint Nordic study 
British Journal of Cancer  2010;102(12):1786-1790.
Background:
Familial nervous system cancers are rare and limited data on familial aspects are available particularly on site-specific tumours.
Methods:
Data from five Nordic countries were used to analyse familial risks of nervous system tumours. Standardised incidence ratios (SIRs) were calculated for offspring of affected relatives compared with offspring of non-affected relatives.
Results:
The total number of patients with nervous system tumour was 63 307, of whom 32 347 belonged to the offspring generation. Of 851 familial patients (2.6%) in the offspring generation, 42 (4.7%) belonged to the families of a parent and at least two siblings affected. The SIR of brain tumours was 1.7 in offspring of affected parents; it was 2.0 in siblings and 9.4 in families with a parent and sibling affected. For spinal tumours, the SIRs were much higher for offspring of early onset tumours, 14.0 for offspring of affected parents and 22.7 for siblings. The SIRs for peripheral nerve tumours were 16.3 in offspring of affected parents, 27.7 in siblings and 943.9 in multiplex families.
Conclusion:
The results of this population-based study on medically diagnosed tumours show site-, proband- and age-specific risks for familial tumours, with implications for clinical genetic counselling and identification of the underlying genes.
doi:10.1038/sj.bjc.6605708
PMCID: PMC2883707  PMID: 20502456
brain tumour; spinal tumour; peripheral nerve tumour; familial risk
6.  Rapid Quantification of Viable Campylobacter Bacteria on Chicken Carcasses, Using Real-Time PCR and Propidium Monoazide Treatment, as a Tool for Quantitative Risk Assessment▿ †  
Applied and Environmental Microbiology  2010;76(15):5097-5104.
A number of intervention strategies against Campylobacter-contaminated poultry focus on postslaughter reduction of the number of cells, emphasizing the need for rapid and reliable quantitative detection of only viable Campylobacter bacteria. We present a new and rapid quantitative approach to the enumeration of food-borne Campylobacter bacteria that combines real-time quantitative PCR (Q-PCR) with simple propidium monoazide (PMA) sample treatment. In less than 3 h, this method generates a signal from only viable and viable but nonculturable (VBNC) Campylobacter bacteria with an intact membrane. The method's performance was evaluated by assessing the contributions to variability by individual chicken carcass rinse matrices, species of Campylobacter, and differences in efficiency of DNA extraction with differing cell inputs. The method was compared with culture-based enumeration on 50 naturally infected chickens. The cell contents correlated with cycle threshold (CT) values (R2 = 0.993), with a quantification range of 1 × 102 to 1 × 107 CFU/ml. The correlation between the Campylobacter counts obtained by PMA-PCR and culture on naturally contaminated chickens was high (R2 = 0.844). The amplification efficiency of the Q-PCR method was not affected by the chicken rinse matrix or by the species of Campylobacter. No Q-PCR signals were obtained from artificially inoculated chicken rinse when PMA sample treatment was applied. In conclusion, this study presents a rapid tool for producing reliable quantitative data on viable Campylobacter bacteria in chicken carcass rinse. The proposed method does not detect DNA from dead Campylobacter bacteria but recognizes the infectious potential of the VBNC state and is thereby able to assess the effect of control strategies and provide trustworthy data for risk assessment.
doi:10.1128/AEM.00411-10
PMCID: PMC2916463  PMID: 20562292
7.  Autoimmune disease and risk for Parkinson disease 
Neurology  2009;73(18):1462-1468.
Objective:
Inflammatory mediators are increased in autoimmune diseases and may activate microglia and might cause an inflammatory state and degeneration of dopaminergic neurons in the brain. Thus, we evaluated whether having an autoimmune disease increases the risk for developing Parkinson disease (PD).
Methods:
A population based case-control study was conducted in Denmark of 13,695 patients with a primary diagnosis of PD recorded in the Danish National Hospital Register during the period 1986–2006. Each case was matched on year of birth and sex to 5 population controls selected at random from among inhabitants of Denmark who were alive at the date of the patient's diagnosis. The main exposure measure was a hospital diagnosis of 1 of 32 selected autoimmune diseases recorded 5 or more years before the index date in the files of the Danish Hospital Register.
Results:
We observed no overall association between a diagnosis of autoimmune disease and risk for subsequent PD (odds ratio 0.96, 95% confidence interval 0.85–1.08). In a subgroup of patients with autoimmune diseases with systemic involvement, primarily rheumatoid arthritis, we saw a decrease in risk for PD of 30%.
Conclusions:
Our results do not support the hypothesis that autoimmune diseases increase the risk for Parkinson disease. The decreased risk observed among patients with rheumatoid arthritis might be explained by underdiagnosis of movement disorders such as Parkinson disease in this patient group or by a protective effect of the treatment with anti-inflammatory drugs over prolonged periods.
GLOSSARY
= confidence interval;
= chronic obstructive pulmonary disease;
= International Classification of Diseases, 8th revision;
= nonsteroidal anti-inflammatory drug;
= odds ratio;
= Parkinson disease.
doi:10.1212/WNL.0b013e3181c06635
PMCID: PMC2779008  PMID: 19776374
8.  Proton pump inhibitors and risk of gastric cancer: a population-based cohort study 
British Journal of Cancer  2009;100(9):1503-1507.
Proton pump inhibitor (PPI) use leads to hypergastrinaemia, which has been associated with gastrointestinal neoplasia. We evaluated the association between PPI use and risk of gastric cancer using population-based health-care registers in North Jutland, Denmark, during 1990–2003. We compared incidence rates among new users of PPI (n=18 790) or histamine-2-antagonists (H2RAs) (n=17 478) and non-users of either drug. Poisson regression analysis was used to estimate incidence rate ratios (IRRs) adjusted for multiple confounders. We incorporated a 1-year lag time to address potential reverse causation. We identified 109 gastric cancer cases among PPI users and 52 cases among H2RA users. After incorporating the 1-year lag time, we observed IRRs for gastric cancer of 1.2 (95% CI: 0.8–2.0) among PPI users and 1.2 (95% CI: 0.8–1.8) among H2RA users compared with non-users. These estimates are in contrast to significant overall IRRs of 9.0 and 2.8, respectively, without the lag time. In lag time analyses, increased IRRs were observed among PPI users with the largest number of prescriptions or the longest follow-up compared with H2RA users or non-users. Although our results point to a major influence of reverse causation and confounding by indication on the association between PPI use and gastric cancer incidence, the finding of increased incidence among PPI users with most prescriptions and longest follow-up warrants further investigation.
doi:10.1038/sj.bjc.6605024
PMCID: PMC2694435  PMID: 19352380
stomach neoplasms; proton pump inhibitors; histamine-2-antagonists; risk; cohort study
9.  Wheezing, asthma, hay fever, and atopic eczema in relation to maternal occupations in pregnancy 
Objectives
To examine whether prenatal occupational exposures, especially to organic solvents, are associated with atopic diseases in childhood.
Methods
The study comprised children born in Odense or Aalborg, Denmark between 1984 and 1987. Occupational job titles were derived from questionnaires filled out by the mothers when attending midwife centres. Assessment of organic solvent exposures was based on job titles selected by occupational specialists. A follow up questionnaire to the parents provided data on medical diagnoses as well as wheezing symptoms for 7844 children aged 14–18. Multivariate logistic regression analyses were performed to estimate the cumulative risk for wheezing (early wheezing not diagnosed as asthma), asthma, hay fever, and atopic eczema during childhood by means of odds ratios (OR) and 95% confidence intervals (CI).
Results
Explorative analyses by maternal job titles in pregnancy showed elevated odds ratios concerning different atopic diseases for occupational groups such as “bakers, pastry cooks, and confectionary makers”, “dental assistants”, “electrical and electronic assemblers”, “sewers and embroiders”, and “bookbinders and related workers”. An excess risk ratio for hay fever (OR 2.8, CI 1.1 to 7.5) was found following maternal gestational exposure to organic solvents. Furthermore, a slightly raised odds ratio for asthma was observed in children of shift workers (OR 1.2, CI 1.0 to 1.5).
Conclusion
The data suggest links between certain maternal occupations during pregnancy and atopic diseases, which merits further scrutiny. However, no consistent pattern was seen across the different atopic diseases.
doi:10.1136/oem.2005.024422
PMCID: PMC2078155  PMID: 16757508
solvents; prenatal exposure delayed effects; hypersensitivity
10.  Dr. Zompo: an online data repository for Zostera marina and Posidonia oceanica ESTs 
As ecosystem engineers, seagrasses are angiosperms of paramount ecological importance in shallow shoreline habitats around the globe. Furthermore, the ancestors of independent seagrass lineages have secondarily returned into the sea in separate, independent evolutionary events. Thus, understanding the molecular adaptation of this clade not only makes significant contributions to the field of ecology, but also to principles of parallel evolution as well. With the use of Dr. Zompo, the first interactive seagrass sequence database presented here, new insights into the molecular adaptation of marine environments can be inferred. The database is based on a total of 14 597 ESTs obtained from two seagrass species, Zostera marina and Posidonia oceanica, which have been processed, assembled and comprehensively annotated. Dr. Zompo provides experimentalists with a broad foundation to build experiments and consider challenges associated with the investigation of this class of non-domesticated monocotyledon systems. Our database, based on the Ruby on Rails framework, is rich in features including the retrieval of experimentally determined heat-responsive transcripts, mining for molecular markers (SSRs and SNPs), and weighted key word searches that allow access to annotation gathered on several levels including Pfam domains, GeneOntology and KEGG pathways. Well established plant genome sites such as The Arabidopsis Information Resource (TAIR) and the Rice Genome Annotation Project are interfaced by Dr. Zompo. With this project, we have initialized a valuable resource for plant biologists in general and the seagrass community in particular. The database is expected to grow together with more data to come in the near future, particularly with the recent initiation of the Zostera genome sequencing project.
The Dr. Zompo database is available at http://drzompo.uni-muenster.de/
doi:10.1093/database/bap009
PMCID: PMC2790305  PMID: 20157482
11.  Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study 
British Journal of Cancer  2008;98(4):728-733.
The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985–1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6–5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8–8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.
doi:10.1038/sj.bjc.6604228
PMCID: PMC2259175  PMID: 18253122
asynchronous contralateral breast cancer; CHEK2*1100delC mutation; genes; radiation therapy; chemotherapy
12.  Use of NSAIDs, smoking and lung cancer risk 
British Journal of Cancer  2007;98(1):232-237.
We investigated the risk of lung cancer in relation to non-steroidal anti-inflammatory drugs (NSAIDs) among 573 cases and 857 sex- and age-matched controls for whom we had information on use of NSAIDs, from a prescription database covering all pharmacies in Denmark since 1995, and self-reported NSAID use, smoking habits and other potential confounders. Associations were expressed as odds ratios, assessed by logistic regression in unmatched analyses. After controlling for smoking habits, length of education and concomitant use of acetaminophen, we found a slightly decreased relative risk of 0.86 (95% confidence intervals, 0.65–1.14) for lung cancer associated with any use of NSAIDs. The risk decreased significantly (P=0.02) with increasing numbers of dispensed prescriptions per year during the 1–3 years before the index date with a relative risk of 0.49 (0.28–0.84) among those with four or more prescriptions per year during this period. Our findings suggest that regular use of NSAIDs is associated with a slightly or moderately reduced risk for lung cancer.
doi:10.1038/sj.bjc.6604151
PMCID: PMC2359699  PMID: 18087276
lung cancer; pharmacoepidemiology; non-steroidal anti-inflammatory drugs; chemoprevention
13.  Laboratory work and pregnancy outcomes: a study within the National Birth Cohort in Denmark 
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.
doi:10.1136/oem.2005.021204
PMCID: PMC2078042  PMID: 16361406
laboratory work; organic solvents; pregnancy outcomes; radioisotopes
14.  Eelgrass Meadows in the California Channel Islands and Adjacent Coast Reveal a Mosaic of Two Species, Evidence for Introgression and Variable Clonality 
Annals of Botany  2007;101(1):73-87.
Background and Aims
Seagrasses are important facilitator species in shallow, soft-bottom marine environments worldwide and, in many places, are threatened by coastal development and eutrophication. One narrow-leaved species (Zostera marina) and one wide-leaved species, variously designated as Z. marina, Z. pacifica or Z. asiatica, are found off the California Channel Islands and adjacent California–Mexico coast. The aim of the present study was to confirm species identification genetically and to link patterns of genetic diversity, connectivity and hybridization among and within the populations with historical sea levels (Ice Age) or the contemporary environment.
Methods
Samples (n = 11–100) were collected from 28 sites off five California Channel Islands and six sites off the adjacent coast of southern California and Baja California, Mexico. DNA polymorphisms of the rDNA-ITS (internal transcribed spacer) cistron (nuclear), the matK intron (chloroplast) and nine microsatellite loci (nuclear) were examined in a population genetic and phylogeographic context.
Key Results
All wide-leaved individuals were Z. pacifica, whereas narrow-leaved forms were Z. marina. Microsatellite genotypes were consistent with hybridization between the two species in three populations. The present distribution of Z. pacifica follows a glacial age land mass rather than present oceanographic regimes, but no link was observed between the present distribution of Z. marina and past or present environments. Island populations of Z. marina often were clonal and characterized by low genotypic diversity compared with populations along the Baja California coast. The high level of clonal connectivity around Santa Catalina Island indicated the importance of dispersal and subsequent re-establishment of vegetative fragments.
Conclusions
The pristine environmental conditions of offshore islands do not guarantee maximum genetic diversity. Future restoration and transplantation efforts of seagrasses must recognize cryptic species and consider the degree of both genetic and genotypic variation in candidate donor populations.
doi:10.1093/aob/mcm288
PMCID: PMC2701847  PMID: 18006507
Clonality; eelgrass; genetic structure; introgression; Last Glacial Maximum; seagrass; Zostera asiatica; Z. marina; Z. pacifica
15.  The threat to scientific integrity in environmental and occupational medicine 
Over the last century, environmental and occupational medicine has played a significant role in the protection and improvement of public health. However, scientific integrity in this field has been increasingly threatened by pressure from some industries and governments. For example, it has been reported that the tobacco industry manipulated eminent scientists to legitimise their industrial positions, irresponsibly distorted risk and deliberately subverted scientific processes, and influenced many organisations in receipt of tobacco funding. Many environmental whistleblowers were sued and encountered numerous personal attacks. In some countries, scientific findings have been suppressed and distorted, and scientific advisory committees manipulated for political purposes by government agencies. How to respond to these threats is an important challenge for environmental and occupational medicine professionals and their societies. The authors recommend that professional organisations adopt a code of ethics that requires openness from public health professionals; that they not undertake research or use data where they do not have freedom to publish their results if these data have public health implications; that they disclose all possible conflicts; that the veracity of their research results should not be compromised; and that their research independence be protected through professional and legal support. The authors furthermore recommend that research funding for public health not be directly from the industry to the researcher. An independent, intermediate funding scheme should be established to ensure that there is no pressure to analyse data and publish results in bad faith. Such a funding system should also provide equal competition for funds and selection of the best proposals according to standard scientific criteria.
doi:10.1136/oem.2005.021410
PMCID: PMC1740935  PMID: 16299092
16.  Psychosocial and physical work environment, and risk of pelvic pain in pregnancy. A study within the Danish national birth cohort 
Objective: The sparse knowledge of the aetiology of pelvic pain in pregnancy makes evidence based prevention a limited option. The aim of this study was to examine the relation between pelvic pain in pregnancy and physical and psychosocial working conditions.
Methods: This study used self reported data on working conditions for 1219 cases and 1539 controls, sampled as a nested case-control study within the Danish national birth cohort. Cases and controls were selected on the basis of self reported pelvic pain intensity, pain localisation, and pain impact on daily living activities. Exposure data were collected prospectively; early in pregnancy and before the onset of pelvic pain. Main outcome measures were odds ratios for pelvic pain in pregnancy as a function of physical and psychosocial working conditions.
Results: Pregnant women with fixed evening work and with rotating shifts (without night shift) had odds ratios for pelvic pain in pregnancy of 1.76 (95% confidence intervals 1.04 to 2.96) and 1.65 (1.22 to 2.24), respectively, compared with women with day work. Physically strenuous work was associated with an almost 50% increased risk of pelvic pain in pregnancy (1.47; 1.17 to 1.84). In women who were under high psychosocial strain at work odds ratio was 1.39 (1.12 to 1.74) compared with women with low job strain.
Conclusion: Both physically and psychosocially demanding working conditions, measured by physically strenuous work, rotating shifts, and high job strain, are associated with an increased reporting of pelvic pain in pregnancy.
doi:10.1136/jech.2004.029520
PMCID: PMC1757090  PMID: 15965142
17.  Leisure time physical exercise during pregnancy and the risk of miscarriage: a study within the Danish National Birth Cohort 
Bjog   2007;114(11):1419-1426.
Objective
To examine the association between leisure time physical exercise during pregnancy and the risk of miscarriage.
Design
Prospective study with elements of retrospective data collection.
Setting
Denmark 1996–2002.
Population
A total of 92 671 pregnant women enrolled in the Danish National Birth Cohort and interviewed subsequently.
Methods
Data on exercise during pregnancy and potential confounders were obtained through computer-assisted telephone interviews either during pregnancy or after an early miscarriage. Outcome of pregnancy was identified by register linkage. Using Cox regression analysis, we estimated the hazard ratio (HR) of miscarriage according to weekly amount of exercise and the type of exercise. The HR was estimated for <11, 11–14, 15–18, and 19–22 weeks of gestation, respectively.
Main outcome measures
Miscarriage, defined as fetal loss before 22 completed weeks of gestation.
Results
A stepwise increasing relation was found between amount of exercise and risk of miscarriage, where risk of miscarriage increased by amount of exercise up to HR = 3.7 (95% CI 2.9–4.7) for women who exercised more than 7 hours per week compared with nonexercisers. Particularly ‘high-impact exercise’ was associated with an increased risk of miscarriage. No association was seen between exercise and risk of miscarriage after 18 weeks of gestation.
Conclusions
This study suggests that exercise early in pregnancy is associated with an increased risk of miscarriage. The results should, however, be interpreted cautiously as potential bias arising from retrospective data collection may explain part of the association.
Please cite this paper as: Madsen M, Jørgensen T, Jensen M, Juhl M, Olsen J, Andersen P, Nybo Andersen A. Leisure time physical exercise during pregnancy and the risk of miscarriage: a study within the Danish National Birth Cohort. BJOG 2007;114:1419–1426.
doi:10.1111/j.1471-0528.2007.01496.x
PMCID: PMC2366024  PMID: 17877774
Cohort study; fetal death; physical exercise; pregnancy
18.  Activation of nuclear factor κB in colonic mucosa from patients with collagenous and ulcerative colitis 
Gut  2005;54(4):503-509.
Background and aims: Expression of inducible nitric oxide synthase (iNOS) is greatly upregulated in the colonic mucosa of patients with collagenous and ulcerative colitis. As the transcription factor nuclear factor κB (NFκB) is a major inducer of iNOS gene expression, we compared activation and transcriptional activity of NFκB in colonic mucosal biopsies from these patients.
Patients: Eight patients with collagenous colitis, six with relapsing ulcerative colitis, and eight with uninflamed bowel were studied.
Methods: NFκB DNA binding activity was assessed by electrophoretic mobility shift assay and inhibitor of NFκB (IκB) kinase (IKK) activity by immunocomplex kinase assay. In vivo recruitment of NFκB to the iNOS promoter was determined by chromatin immunoprecipitation analysis and transcriptional activity by NFκB gene expression profiling arrays. Cells showing NFκB activation were identified by immunohistochemistry.
Results: In collagenous and ulcerative colitis, as opposed to uninflamed bowel, IKKβ activity and strong NFκB DNA binding gave rise to activation of identical NFκB subunits and recruitment of transcriptionally active p65 to the iNOS promoter. In collagenous colitis, activated NFκB was observed only in epithelial cells while up to 10% of lamina propria macrophages showed activation in ulcerative colitis.
Conclusions: In collagenous and ulcerative colitis, colonic mucosal NFκB is activated and recruited to the iNOS promoter in vivo via an IKKβ mediated pathway. As collagenous colitis is not associated with tissue injury, these data challenge the prevailing view that activation of NFκB per se mediates tissue injury. Our results suggest that downstream inflammatory reactions leading to tissue damage originate in lamina propria immune cells, as increased NFκB activity in collagenous colitis was localised solely in epithelial cells, but present also in macrophages in ulcerative colitis.
doi:10.1136/gut.2003.034165
PMCID: PMC1774469  PMID: 15753535
collagenous colitis; inflammatory bowel disease; nitric oxide synthase; nuclear factor κB; ulcerative colitis
19.  G2 chromosomal radiosensitivity in Danish survivors of childhood and adolescent cancer and their offspring 
British Journal of Cancer  2005;93(9):1038-1045.
In order to investigate the relationship between chromosomal radiosensitivity and early-onset cancer, the G2 chromosomal radiosensitivity assay was undertaken on a group of 23 Danish survivors of childhood and adolescent cancer, a control group comprising their partners and a group of 38 of their offspring. In addition, the previously reported in-house control group from Westlakes Research Institute (WRI) was extended to 27 individuals. When using the 90th percentile cutoff for the WRI control group, the proportion of individuals with elevated radiosensitivity was 11, 35, 52 and 53% for the WRI control, partner control, cancer survivor and the offspring groups, respectively, with significant differences between the WRI control group and the cancer survivor group (P=0.002) and the offspring group (P<0.001). However, while the comparisons with the WRI control group support an association of chromosomal radiosensitivity with cancer predisposition, when the partner control group was used to define the radiosensitivity cutoff point, no significant differences in radiosensitivity profiles were found between the partner control group and either the cancer survivor group or the offspring group. The failure to distinguish between the G2 aberration profiles of the apparently normal group of partners and the cancer survivor group suggests that any association with cancer should be viewed with caution, but also raises questions as to the suitability of the partners of cancer survivors to act as an appropriate control group. Heritability of the radiosensitive phenotype was examined by segregation analysis of the Danish families and suggested that 67.3% of the phenotypic variance of G2 chromosomal radiosensitivity is attributable to a putative major gene locus with dominant effect.
doi:10.1038/sj.bjc.6602807
PMCID: PMC2361675  PMID: 16234827
chromosomal radiosensitivity; childhood and adolescent cancer; inherited predisposition
20.  The risk of a second cancer after hospitalisation for venous thromboembolism 
British Journal of Cancer  2005;93(7):838-841.
Although venous thromboembolism (VTE) is common in patients with cancer, it is not known if it is associated with risk of a second malignancy. Using the Danish Cancer Registry and National Registry of Patients, we studied a population-based cohort of 6285 patients with cancer who had an episode of VTE. The risk of a second cancer was compared with that among 30 713 cancer patients without VTE, matched for age, sex, cancer site and year of diagnosis. Overall, the relative risk for a second cancer diagnosis was 1.3 (95% confidence interval (CI) 1.1–1.4). However, the excess risk varied with the time from the initial cancer diagnosis to the thrombotic event. If the thrombotic episode occurred within the first year, the relative risk for a second cancer was 1.0 (95% CI 0.9–1.3), but if the VTE occurred more than 1 year after the initial cancer, the overall relative risk for a second cancer was 1.4 (95% CI 1.2–1.7), with strong associations for cancers of the digestive organs, ovary and prostate. The association between VTE and subsequent incident cancer extends to patients who already have had a cancer diagnosis.
doi:10.1038/sj.bjc.6602757
PMCID: PMC2361646  PMID: 16136048
venous thromboembolism; epidemiology; prognosis; risk
22.  Shift work and subfecundity: a causal link or an artefact? 
Methods: From 1 March 1998 to 1 May 2000, 39 913 pregnant women were enrolled in the DNBC. Data on job characteristics and TTP (0–2, 3–5, 6–12, and >12 months) were used for 17 531 daytime workers and 3907 shift workers who had planned the pregnancy. Fecundity odds ratios (ORs) were calculated with 95% confidence intervals using the discrete time survival analysis techniques performed by logistic regression. An OR above 1 expresses a shorter TTP and then a higher fecundity. Potential confounders, such as age at conception, gravidity, prepregnant body mass index, smoking, and alcohol consumption, as well as occupational characteristics, were also included in the model.
Results: Fixed evening workers and fixed night workers had a longer TTP. Compared with daytime workers, the adjusted ORs were 0.80 (95% CI 0.70 to 0.92) for fixed evening workers, 0.80 (95% CI 0.63 to 1.00) for fixed night workers, 0.99 (95% CI 0.91 to 1.07) for rotating shift (without night) workers, and 1.05 (95% CI 0.97 to 1.14) for rotating shift (with night) workers. When analysis was restricted to nulliparous women, the estimates remained unchanged. The proportions of unplanned pregnancies and contraceptive failures were higher among fixed evening and fixed night workers.
Conclusions: There was no unequivocal evidence of a causal association between shift work and subfecundity. The slightly reduced fecundity among fixed evening workers and fixed night workers may be mediated by pregnancy planning bias or differential options for sexual contacts.
doi:10.1136/oem.60.9.e12
PMCID: PMC1740621  PMID: 12937208
23.  Pre-eclampsia and febrile convulsions 
Archives of Disease in Childhood  2003;88(8):726-727.
doi:10.1136/adc.88.8.726
PMCID: PMC1719617  PMID: 12876175
24.  Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia 
British Journal of Cancer  2005;93(2):260-265.
Epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia (AT), a rare autosomal recessive disease. A large proportion of the members of AT families are carriers of AT-causing gene mutations in ATM (Ataxia Telangiectasia Mutated), and it has been hypothesised that these otherwise healthy carriers are predisposed to breast cancer. This is an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT in 66 Nordic families. Blood relatives were identified through population registry linkages, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. The ATM mutation carrier probabilities of relatives were assigned from the combined information on location in family, consanguinity, if any, and supplementary carrier screening in some families. Among the 1445 blood relatives of AT patients, 225 cancers were observed, with 170.4 expected, yielding a standardised incidence ratio (SIR) of 1.3 (95% confidence interval (CI), 1.1–1.4). Invasive breast cancer occurred in 34 female relatives (SIR, 1.7; 95% CI, 1.2–2.4) and was diagnosed in 21 women before the age of 55 years (SIR, 2.9; 95% CI, 1.8–4.5), including seven mothers of probands (SIR, 8.1; 95% CI, 3.3–17). When the group of mothers was excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. We concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. The findings of breast cancer risk in mothers, but not other likely mutation carriers, in this and other studies raises questions about the hypothesis of a simple causal relationship with ATM heterozygosity.
doi:10.1038/sj.bjc.6602658
PMCID: PMC2361547  PMID: 15942625
ATM heterozygosity; early-onset breast cancer; cancer predisposition; familial cancer
25.  Hormone use for menopausal symptoms and risk of breast cancer. A Danish cohort study 
British Journal of Cancer  2005;92(7):1293-1297.
Numerous studies and meta-analyses have shown that hormone replacement therapy (HRT) for menopausal symptoms increases the risk of developing breast cancer, estimated to be 2.3% for each year of use. The influence of different oestrogen–progestin regimens has still not been fully evaluated. Using longitudinal data from the population-based prescription database of the county of North Jutland, Denmark, and the Danish Cancer Registry, we examined the risk of developing breast cancer in relation to HRT in a cohort of 78 380 women aged 40–67 years from 1989 to 2002. A total of 1462 cases of breast cancer were identified during a mean follow-up of 10 years. Use of HRT did not increase the risk of breast cancer in women aged 40–49 years. Restricting the cohort to 48 812 women aged 50 years or more at entry, of whom 15 631 were HRT users, we found an increased risk associated with current use of HRT (relative risk 1.61, 95% confidence interval 1.38–1.88). The risk increased with increasing duration of use and decreased with time since last HRT prescription, reaching unity after 5 years. No material risk difference was observed among the various HRT-regimens. This population-based cohort study provides further confirmation that HRT increases the risk of developing breast cancer in women aged 50 years or more.
doi:10.1038/sj.bjc.6602472
PMCID: PMC2361963  PMID: 15785751
hormone replacement therapy; breast cancer; population-based study

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