Trends in coronary risk factors in the WHO MONICA Project

Background. The World Health Organization (WHO) MONICA Project was established to determine how trends in event rates for coronary heart disease (CHD) and, optionally, stroke were related to trends in classic coronary risk factors. Risk factors were therefore monitored over ten years across 38 populations from 21 countries in four continents (overall period covered: 1979-1996). Methods. A standard protocol was applied across participating centres, in at least two, and usually three, independent surveys conducted on random samples of the study populations, well separated within the 10-year study period. Results. Smoking rates decreased in most male populations (35-64 years) but in females the majority showed increases. Systolic blood pressure showed decreasing trends in the majority of centres in both sexes. Mean levels of cholesterol generally showed downward trends, which, although the changes were small, had large effects on risk. There was a trend of increasing body mass index (BMI) with half the female populations and two-thirds of the male populations showing a significant increase. Conclusions. It is feasible to monitor the classic CHD risk factors in diverse populations through repeated surveys over a decade. In general, the risk factor trends are downwards in most populations but in particular, an increase in smoking in women in many populations and increasing BMI, especially in men, are worrying findings with significant public health implications.

Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes

Objective Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), N -(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE-). Results In DM PE+ versus DM PE-, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P <0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE:hydroimidazolone was significantly lower in the second trimester (P <0.05) and sRAGE:AGE and sRAGE:CML tended to be lower in the first trimester (P <0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM. © 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.

Apolipoprotein-defined lipoproteins and apolipoproteins:Associations with abnormal albuminuria in type 1 diabetes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort

Dyslipoproteinemia has been associated with nephropathy in diabetes, with stronger correlations in men than in women. We aimed to characterize and compare plasma lipoprotein profiles associated with normal and increased albuminuria in men and women using apolipoprotein-defined lipoprotein subclasses and simple apolipoprotein measures.

Maternal Vitamin D Status in Type 1 Diabetic Pregnancy: Impact on Neonatal Vitamin D Status and Association with Maternal Glycaemic Control

Objective: The first aim of this study was to assess 25-hydroxy vitamin D (25OHD) concentrations in women with type 1 diabetes (T1DM) during pregnancy, post-delivery and also foetal (cord blood) 25OHD concentrations and to examine relationships between these. The second aim of the study was to investigate potential interactions between maternal body mass index (BMI) and foetal vitamin D status. A further study aim was to examine potential relationships between maternal 25OHD and glycosylated haemoglobin (HbA_1c) throughout pregnancy.

Research Design and Methods: This was an observational study of 52 pregnant controls without diabetes and 65 pregnant women with T1DM in a university teaching hospital. Maternal serum 25OHD was measured serially throughout the pregnancy and post-delivery. Cord blood 25OHD was measured at delivery. 25OHD was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS).

Results: Vitamin D deficiency (25OHD <25 nmol/L) was apparent in both the T1DM subjects and controls at all 3 pregnancy trimesters. Vitamin D levels in all cord blood were <50 nmol/L. Maternal 25OHD correlated positively with cord 25OHD at all 3 trimesters in the T1DM group (p= 0.02; p<0.001; p<0.001). 25OHD levels within cord blood were significantly lower for women with diabetes classified as obese vs. normal weight at booking [normal weight BMI <25 kg/m² vs. obese BMI >30 kg/m² (nmol/L±SD); 19.93±11.15 vs. 13.73±4.74, p= 0.026]. In the T1DM group, HbA_1c at booking was significantly negatively correlated with maternal 25OHD at all 3 trimesters (p= 0.004; p = 0.001; p= 0.05).

Conclusion: In T1DM pregnancy, low vitamin D levels persist throughout gestation and post-delivery. Cord blood vitamin D levels correlate with those of the mother, and are significantly lower in obese women than in their normal weight counterparts. Maternal vitamin D levels exhibit a significant negative relationship with HbA_1c levels, supporting a potential role for this vitamin in maintaining glycaemic control. 

Serum Inflammatory Markers and Preeclampsia in Type 1 Diabetes:A prospective study

OBJECTIVE Inflammation and endothelial dysfunction have been associated with the immunobiology of preeclampsia (PE), a significant cause of adverse pregnancy outcomes. The prevalence of PE is elevated several fold in the presence of maternal type 1 diabetes mellitus (T1DM). Although cross-sectional studies of pregnancies among women without diabetes have shown altered inflammatory markers in the presence of PE, longitudinal studies of diabetic women are lacking. In maternal serum samples, we examined the temporal associations of markers of inflammation with the subsequent development of PE in women with T1DM. RESEARCH DESIGN AND METHODS We conducted longitudinal analyses of serum C-reactive protein (CRP), adhesion molecules, and cytokines during the first (mean ± SD, 12.2 ± 1.9 weeks), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy (visits 1-3, respectively). All study visits took place before the onset of PE. Covariates were BMI, HbA1c, age of onset, duration of diabetes, and mean arterial pressure. RESULTS In women with T1DM who developed PE versus those who remained normotensive, CRP tended to be higher at visits 1 (P = 0.07) and 2 (P = 0.06) and was significantly higher at visit 3 (P <0.05); soluble E-selectin and interferon-?-inducible protein-10 (IP-10) were significantly higher at visit 3; interleukin-1 receptor antagonist (IL-1ra) and eotaxin were higher and lower, respectively, at visit 2 (all P <0.05). These conclusions persisted following adjustment for covariates. CONCLUSIONS In pregnant women with T1DM, elevated CRP, soluble E-selectin, IL-1ra, and IP-10 and lower eotaxin were associated with subsequent PE. The role of inflammatory factors as markers and potential mechanisms of the high prevalence of PE in T1DM merits further investigation.

LDL-containing immune complexes in the DCCT/EDIC cohort:associations with lipoprotein subclasses

Immune complexes containing modified LDL (LDL-IC) and NMR-determined Total LDL particle concentrations are significantly associated with intima-media thickness (IMT). We analyzed the associations between concentrations of NMR-determined lipoprotein subclasses and LDL-IC in the DCCT/EDIC cohort. LDL-IC concentrations in women and men of the DCCT/EDIC cohort did not differ significantly and were positively associated with Total LDL particle concentrations in men and women (r=0.34, r=0.32, respectively; P

Interventions for enhancing adherence to treatment in adults with bronchiectasis

Background: Bronchiectasis is characterised by a widening of the airways, leading to excess mucus production and recurrent infection. It is more prevalent in women and those in middle age. Many patients with bronchiectasis do not adhere to treatments (medications, exercise and airway clearance) prescribed for their condition. The best methods to change these adherence behaviours have not been identified.
Objectives: To assess the effects of interventions to enhance adherence to any aspect of treatment in adults with bronchiectasis in terms of adherence and health outcomes, such as pulmonary exacerbations, health-related quality of life and healthcare costs.
Search methods:We searched the Cochrane Airways Gr oup Specialised Register (CAGR), which contains trial reports identified through systematic searches of CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, from inception to October 2015.
Selection criteria: We planned to include randomised controlled trials (RCTs) of adults with bronchiectasis that compared any intervention aimed at enhancing adherence versus no intervention, usual care or another adherence intervention. We excluded studies of those who had bronchiectasis due to cystic fibrosis.
Data collection and analysis: Two review authors (AMcC and ET) independently screened titles, abstracts and full-texts of identified studies.
Main results: Searches retrieved 36 studies reported in 37 articles; no eligible studies were identified.
Author's Conclusions: We did not identify any studies that assessed the effect of interventions to enhance adherence to treatment in bronchiectasis. Adequately powered, well-designed trials of adherence interventions for bronchiectasis are needed.

A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.

Methods: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.

Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).

Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

Sentinel lymph node biopsy in breast cancer - is lymphoscintigraphy really necessary?

The role of lymphoscintigraphy in sentinel node biopsy in breast cancer remains debatable. This study assesses the value of lymphoscintigraphy in axillary sentinel node biopsy in women undergoing surgery for breast cancer. Sixty-two patients underwent sentinel node biopsy using a combination of technetium-label led nanocolloid, lymphoscintigraphy and patent blue dye. Lymphoscintigraphy was successful in 84% of patients. Axillary sentinel nodes were identified intraoperatively in all these patients. Internal mammary nodes were identified on lymphoscintigraphy in 19%. Despite lymphoscintigraphy being unsuccessful in 10 patients, axillary sentinel nodes were found intraoperatively in eight of these patients. Lymphoscintigraphy did not increase the detection rate of axillary sentinel nodes and a negative scan did not preclude identification of an axillary sentinel node intraoperatively. This study questions the contribution of lymphoscintigraphy in axillary sentinel node biopsy, however its value may lie in the detection of extra-axillary nodes. (C) 2002 Published by Elsevier Science Ltd.

Commissioned Research on HPV Frequency in Cervical Cancers and Premalignant lesions of the Cervix

This report documents an investigation of the frequency of human papillomavirus (HPV) genotypes across cervical disease states in Northern Ireland ranging from koilocytosis to cervical cancer. It builds upon earlier work by the Northern Ireland HPV Working Group which reported a HPV prevalence of 17.1% overall in women aged 20-65 years irrespective of pathology and 13.2% among women in the screening age group (20-60 years) with normal cytology (Anderson et al. 2012, Anderson et al. 2013).

Development of a continuing professional development website to raise awareness of preconception counselling and pre-pregnancy care for Women with Diabetes

Aims: Pre-pregnancy care reduces the risk of adverse pregnancy outcomes in women with diabetes, yet the majority of women receive suboptimal care due to poor preconception counselling rates and a lack of awareness about the importance of specialised pre-pregnancy care. The primary aim was to develop a continuing professional development (CPD) resource for healthcare professionals (HCPs) who work with women with diabetes to facilitate preconception counselling with this group.

Methods: The website was developed under the direction of a multidisciplinary team, adhering to NICE guidelines. The tone, key messages and format are informed by the “Women with Diabetes” preconception counselling website, www.womenwithdiabetes.net, an existing resource which is effective in helping women to be better prepared for pregnancy.Results: This e-learning resource will give HCPs the necessary knowledge and tools to prepare women with diabetes to plan for pregnancy. The website features women with diabetes sharing their views and experiences, alongside an evidence-based commentary and key messages from research papers and clinical guidelines. It comprises two modules: “Planning for Pregnancy”, focusing on contraception, risks and planning; and “Diabetes and Pregnancy”, focusing on support during pregnancy with an overview of each trimester of pregnancy.

Conclusion: This website will be a useful CPD resource for all HCPs working with women with diabetes, providing a certificate on completion. This resource will empower HCPs to engage in preconception counselling with women with diabetes by providing the HCP with a greater understanding of the specific needs of women with diabetes both preconception and during pregnancy.

National trends in main causes of hospitalization: a multi-cohort register study of the Finnish working-age population, 1976-2010

Principal Findings: Over the period of 35 years, the risk of hospitalization for cardiovascular diseases and respiratory diseases decreased. Hospitalization for musculoskeletal diseases increased whereas mental and behavioral hospitalizations slightly decreased. The risk of cancer hospitalization decreased marginally in men, whereas in women an upward trend was observed.

Conclusions/Significance: A considerable health transition related to hospitalizations and a shift in the utilization of health care services of working-age men and women took place in Finland between 1976 and 2010.

Background: The health transition theory argues that societal changes produce proportional changes in causes of disability and death. The aim of this study was to identify long-term changes in main causes of hospitalization in working-age population within a nation that has experienced considerable societal change.

Methodology: National trends in all-cause hospitalization and hospitalizations for the five main diagnostic categories were investigated in the data obtained from the Finnish Hospital Discharge Register. The seven-cohort sample covered the period from 1976 to 2010 and consisted of 3,769,356 randomly selected Finnish residents, each cohort representing 25% sample of population aged 18 to 64 years.

Novel Hypoxia-Associated Markers of Chemoresistance in Ovarian Cancer

Background:
Ovarian cancer is the fifth leading cause of cancer in women and has poor
long-term survival, in part, due to chemoresistance. Tumour hypoxia is associated with
chemoresistance in ovarian cancer. However, relatively little is known about the genes
activated in ovarian cancer which cause chemoresistance due to hypoxia. This study
aimed to firstly identify genes whose expression is associated with hypoxia-induced
chemoresistance, and secondly select hypoxia-associated biomarkers and evaluate their
expression in ovarian tumours.
Design:
Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer
cell lines were exposed to combinations of hypoxia and/or cisplatin as part of a matrix
designed to reflect clinically relevant scenarios. RNA was extracted and interrogated
on Affymetrix Human Gene arrays. Differential gene expression was analysed for cells
exposed to hypoxia and/or treated with cisplatin. Potential markers of chemoresistance
were selected for evaluation in a cohort of ovarian tumour samples by R
T-PCR.
Results:
A wide range of genes associated with chemoresistance were differentially
expressed in cells exposed to hypoxia and/or cisplatin. Selected genes [ANGPTL4,
HER3 and HIF-1
α
] were chosen for further validation in a cohort of ovarian tumour
samples. High expression of ANGPTL4 trended towards reduced progression-free and
overall survival. High expression of HER3 trended to increased progression-free but
reduced overall survival, while high expression of HIF-1
α
trended towards reduced
progression-free and increased overall survival.
Conclusions:
In conclusion, this study has further characterized the relationship between
hypoxia and chemoresistance in an ovarian cancer model. We have also identified many
potential biomarkers of hypoxia and platinum resistance and provided initial validation
of a subset of these markers in ovarian cancer tissues.

Making space: English women, letter-writing, and the life of the mind, c.1650-1750

This article uses women's letter-writing from the late seventeenth and early eighteenth centuries to explore the home as a site of female intellectual endeavour. Far from representing a static backdrop to the action of domestic life, the home played a dynamic role in women's experiences of the life of the mind and shaped the ways in which women thought and wrote. Letters were penned in dining rooms, parlours and closets, by firesides, and on desks and laps. In their letters, women projected images of themselves scribbling epistles to friends in order to maintain their mental intimacy. Space was both real and imagined and the physical realities of a hand-written and hand-delivered letter gave way to the imaginative possibilities brought by networks of epistolary exchange and the alternative spaces of creative thought. By reinstating the home more fully in the history of female intellectual experience, a more nuanced view of the domestic arena can be developed: one that sees the home not as a site of exclusion and confinement, but as a space for scholarship and exchange. 

Exposure to aflatoxin B1 in utero is associated with DNA methylation in white blood cells of infants in The Gambia

BACKGROUND: Exposure to environmental toxins during embryonic development may lead to epigenetic changes that influence disease risk in later life. Aflatoxin is a contaminant of staple foods in sub-Saharan Africa, is a known human liver carcinogen and has been associated with stunting in infants.

METHODS: We have measured aflatoxin exposure in 115 pregnant women in The Gambia and examined the DNA methylation status of white blood cells from their infants at 2-8 months old (mean 3.6 ± 0.9). Aflatoxin exposure in women was assessed using an ELISA method to measure aflatoxin albumin (AF-alb) adducts in plasma taken at 1-16 weeks of pregnancy. Genome-wide DNA methylation of infant white blood cells was measured using the Illumina Infinium HumanMethylation450beadchip.

RESULTS: AF-alb levels ranged from 3.9 to 458.4 pg/mg albumin. We found that aflatoxin exposure in the mothers was associated to DNA methylation in their infants for 71 CpG sites (false discovery rate < 0.05), with an average effect size of 1.7% change in methylation. Aflatoxin-associated differential methylation was observed in growth factor genes such as FGF12 and IGF1, and immune-related genes such as CCL28, TLR2 and TGFBI. Moreover, one aflatoxin-associated methylation region (corresponding to the miR-4520b locus) was identified.

CONCLUSIONS: This study shows that maternal exposure to aflatoxin during the early stages of pregnancy is associated with differential DNA methylation patterns of infants, including in genes related to growth and immune function. This reinforces the need for interventions to reduce aflatoxin exposure, especially during critical periods of fetal and infant development.