Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias and phthalate load: a large case-control study

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccessibility. We have used a large national biobank of amniotic fluid samples collected at routine amniocentesis to determine the impacts of exogenous endocrine disruptor load on specific fetal biomarkers at this critical time. While adrenal and testicular steroids are highly correlated, they are also mostly positively influenced by increasing phthalate load, represented by the metabolites 7cx-MMeHP and 5cx-MEPP, by PFOS exposure, and by smoking, suggesting an adrenal stress response. In contrast, the testis specific biomarkers INSL3 and androstenedione are negatively impacted by the phthalate endocrine disruptors. Using a case-control design, we show that cryptorchidism and hypospadias are both significantly associated with increased amniotic concentration of INSL3 during gestational weeks 13 to 16, and some, though not all steroid biomarkers. Cases are also linked to a specifically increased variance in the Leydig cell biomarker INSL3 compared to controls, an effect exacerbated by maternal smoking. No influence of phthalate metabolites or PFOS was evident on the distribution of cases and controls. Considering that several animal and human studies have shown a negative impact of phthalate load on fetal and cord blood INSL3, respectively, the present results suggest that such endocrine disruptors may rather be altering the relative dynamics of testicular development and consequent hormone production, leading to a desynchronization of tissue organization during fetal development. Being born small for gestational age appears not to impact on the testicular biomarker INSL3 in second trimester amniotic fluid

The Incidence of Breast Cancer Recurrence 10-32 Years After Primary Diagnosis

BACKGROUND: Extended, more effective breast cancer treatments have increased the prevalence of long-term survivors. We investigated the risk of late breast cancer recurrence (BCR), 10 years or more after primary diagnosis, and associations between patient and tumor characteristics at primary diagnosis and late BCR up to 32 years after primary breast cancer diagnosis. METHODS: Using the Danish Breast Cancer Group clinical database, we identified all women with an incident early breast cancer diagnosed during 1987-2004. We restricted to women who survived 10 years without a recurrence or second cancer (10-year disease-free survivors) and followed them from 10 years after breast cancer diagnosis date until late recurrence, death, emigration, second cancer, or December 31, 2018. We calculated incidence rates per 1000 person-years and cumulative incidences for late BCR, stratifying by patient and tumor characteristics. Using Cox regression, we calculated adjusted hazard ratios for late BCR accounting for competing risks. RESULTS: Among 36 924 women with breast cancer, 20 315 became 10-year disease-free survivors. Of these, 2595 developed late BCR (incidence rate = 15.53 per 1000 person-years, 95% confidence interval = 14.94 to 16.14; cumulative incidence = 16.6%, 95% confidence interval = 15.8% to 17.5%) from year 10 to 32 after primary diagnosis. Tumor size larger than 20 mm, lymph node–positive disease, and estrogen receptor–positive tumors were associated with increased cumulative incidences and hazards for late BCR. CONCLUSIONS: Recurrences continued to occur up to 32 years after primary diagnosis. Women with high lymph node burden, large tumor size, and estrogen receptor–positive tumors had increased risk of late recurrence. Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches

Danish children born with glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies at birth had an increased risk to develop type 1 diabetes

Objective: A large, population-based case-control cohort was used to test the hypothesis that glutamic acid decarboxylase-65 (GAD65) and islet antigen-2 autoantibodies (IA-2A) at birth predict type 1 diabetes. Design and methods: The design was an individually matched case-control study of all Danish type 1 diabetes patients born between 1981 and 2002 and diagnosed before May 1 2004 (median age at diagnosis was 8.8 years). Dried blood spot samples collected 5 days after birth in the 1981-2002 birth cohorts and stored at -25 degrees C were identified from 2023 patients and from two matched controls (n=4042). Birth data and information on parental age and diabetes were obtained from Danish registers. GAD65A and IA-2A were determined in a radiobinding assay. HLA-DQB1 alleles were analyzed by PCR using time-resolved fluorescence. Results: GAD65A and IA-2A were found in 70/2023 (3.5%) patients compared to 21/4042 (0.5%) controls resulting in a hazard ratio (HR) of 7.49 (P<0.0001). The HR decreased to 4.55 but remained significant (P<0.0003) after controlling for parental diabetes and HLA-DQB1 alleles. Conditional logistic regression analysis showed a HR of 2.55 (P<0.0001) for every tenfold increase in the levels of GAD65A and IA-2A. This HR decreased to 1.93 but remained significant (P<0.001) after controlling for parental diabetes and HLA-DQB1 alleles. Conclusion: These data suggest that GAD65A and IA-2A positivity at birth are associated with an increased risk of developing type 1 diabetes in Danish children diagnosed between 1981 and 2004. European Journal of Endocrinology 164 247-25

Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia: a Danish national birth cohort-based study

Background: Epidemiological studies indicate that having any family member with schizophrenia increases the risk of schizophrenia in the probands. However, genome-wide association studies (GWAS) have accounted for little of this variation. The aim of this study was to use a population-based sample to explore the influence of single-nucleotide polymorphisms (SNPs) on the excess schizophrenia risk in offspring of parents with a psychotic, bipolar affective or other psychiatric disorder

Neonatal vitamin D status and risk of schizophrenia: A population-based case-control study

Context: Clues from the epidemiology of Schizophrenia suggest that low levels of developmental vitamin D may be associated with increased risk of schizophrenia

A sensitive LC/MS/MS assay of 25OH vitamin D₃ and 25OH vitamin D₂ in dried blood spots

Background: Low levels of 25 hydroxyvitamin D (25OHD) during early development is associated with a range of adverse health outcomes. While a number of methods exist to measure 25OHD in sera, none have been specifically developed to examine dried blood spots (DBS)

Type 1 diabetes risk analysis on dried blood spot samples from population-based newborns: design and feasibility of an unselected case-control study

Development of type 1 diabetes mellitus (T1D) may be triggered pre- or perinatally by multiple factors. Identifying new predisposing T1D markers or combinations of markers in a large, well-characterised case-control collection may be important for future T1D prevention. The present work describes the design and feasibility of a large and unselected case-control study, which will define and evaluate prediction criteria for T1D at the time of birth. Danish registries (Biological Specimen Bank for Neonatal Screening, and the National Discharge Registry) made it possible to identify and collect dried blood spots (DBS) from newborns who later developed T1D (cases) born 1981-2002. DBS samples from 2086 cases and two matching control subjects per case were analysed for genetic and immune factors that are associated with T1D: (a) candidate genes (HLA, INS and CTLA4), (b) cytokines and inflammatory markers, (c) islet auto-antibodies (GAD65A, IA-2A). The objective of the study was to define reliable prediction tools for T1D using samples available at the time of birth. In a unique approach, the study linked a large unselected and population-based sample resource to well-ascertained clinical databases and advanced technology. It combined genetic, immunological and demographic data to develop prediction algorithms. It also provided a resource for future studies in which new genetic markers can be included as they are identified