Associations between maternal characteristics and pharmaceutical treatment of gestational diabetes: an analysis of the UK Born in Bradford (BiB) cohort study

Objectives: To identify the maternal characteristics associated with pharmaceutical treatment of gestational diabetes mellitus (GDM). Design: Prospective birth cohort study. Setting: Bradford, UK. Participants: 762 women from the Born in Bradford (BiB) cohort who were treated for GDM in a singleton pregnancy. BiB cohort participants were recruited from 2007 to 2010. All women booked for delivery were screened for GDM between 26 and 28 weeks of gestation using a 75 g 2-hour oral glucose tolerance test (OGTT). Outcome measure: GDM treatment type: lifestyle changes advice (lifestyle changes), lifestyle changes advice with supplementary insulin (insulin) and lifestyle changes advice with supplementary metformin (metformin). Results: 244 (32%) women were prescribed lifestyle changes advice alone while 518 (68%) were offered supplemental pharmaceutical treatment. The odds of receiving pharmaceutical treatment relative to lifestyle changes advice alone were increased for mothers who were obese (OR 4.6, 95% CI 2.8 to 7.5), those who smoked (OR 2.6, 95% CI 1.2 to 5.5) and had higher fasting glucose levels at OGTT (OR 2.1, 95% CI 1.6 to 2.7). The odds of being prescribed pharmaceutical treatment rather than lifestyle changes advice were lower for Pakistani women (OR 0.7, 95% CI 0.4 to 1.0)) than White British women. Relative to insulin treatment, metformin was more likely to be offered to obese women than normal weight women (relative risk ratio, RRR 3.2, 95% CI 1.3 to 7.8) and less likely to be prescribed to women with higher fasting glucose concentrations at OGTT (RRR 0.3, 95% CI 0.2 to 0.6). Conclusions: In the BiB cohort, GDM pharmaceutical treatment tended to be prescribed to women who were obese, White British, who smoked and had more severe hyperglycaemia. The characteristics of metformin-treated mothers differed from those of insulin-treated mothers as they were more likely to be obese but had lower glucose concentrations at diagnosis

Maternal psychological distress in primary care and association with child behavioural outcomes at age three

Observational studies indicate children whose mothers have poor mental health are at increased risk of socio-emotional behavioural difficulties, but it is unknown whether these outcomes vary by the mothers’ mental health recognition and treatment status. To examine this question, we analysed linked longitudinal primary care and research data from 1078 women enrolled in the Born in Bradford cohort. A latent class analysis of treatment status and self-reported distress broadly categorised women as (a) not having a common mental disorder (CMD) that persisted through pregnancy and the first 2 years after delivery (N = 756, 70.1 %), (b) treated for CMD (N = 67, 6.2 %), or (c) untreated (N = 255, 23.7 %). Compared to children of mothers without CMD, 3-year-old children with mothers classified as having untreated CMD had higher standardised factor scores on the Strengths and Difficulties Questionnaire (d = 0.32), as did children with mothers classified as having treated CMD (d = 0.27). Results were only slightly attenuated in adjusted analyses. Children of mothers with CMD may be at risk for socio-emotional and behavioural difficulties. The development of effective treatments for CMD needs to be balanced by greater attempts to identify and treat women. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00787-015-0777-2) contains supplementary material, which is available to authorized users

Nutrient stress alters the glycosylation status of LGR5 resulting in reduced protein stability and membrane localisation in colorectal tumour cells: implications for targeting cancer stem cells

BACKGROUND LGR5 is an important marker of intestinal stem cells and performs its vital functions at the cell membrane. Despite the importance of LGR5 to both normal and cancer stem cell biology, it is not known how microenvironmental stress affects the expression and subcellular distribution of the protein. METHODS Nutrient stress was induced through glucose starvation. Glycosylation status was assessed using endoglycosidase or tunicamycin treatment. Flow cytometry and confocal microscopy were used to assess subcellular distribution of LGR5. RESULTS Glucose deprivation altered the glycosylation status of LGR5 resulting in reduced protein stability and cell surface expression. Furthermore, inhibiting LGR5 glycosylation resulted in depleted surface expression and reduced localisation in the cis-Golgi network. CONCLUSIONS Nutrient stress within a tumour microenvironment has the capacity to alter LGR5 protein stability and membrane localisation through modulation of LGR5 glycosylation status. As LGR5 surface localisation is required for enhanced Wnt signalling, this is the first report to show a mechanism by which the microenvironment could affect LGR5 function

Developing Prediction Equations and a Mobile Phone Application to Identify Infants at Risk of Obesity

Background: Advancements in knowledge of obesity aetiology and mobile phone technology have created the opportunity to develop an electronic tool to predict an infant’s risk of childhood obesity. The study aims were to develop and validate equations for the prediction of childhood obesity and integrate them into a mobile phone application (App). Methods and Findings: Anthropometry and childhood obesity risk data were obtained for 1868 UK-born White or South Asian infants in the Born in Bradford cohort. Logistic regression was used to develop prediction equations (at 6±1.5, 9±1.5 and 12±1.5 months) for risk of childhood obesity (BMI at 2 years >91st centile and weight gain from 0–2 years >1 centile band) incorporating sex, birth weight, and weight gain as predictors. The discrimination accuracy of the equations was assessed by the area under the curve (AUC); internal validity by comparing area under the curve to those obtained in bootstrapped samples; and external validity by applying the equations to an external sample. An App was built to incorporate six final equations (two at each age, one of which included maternal BMI). The equations had good discrimination (AUCs 86–91%), with the addition of maternal BMI marginally improving prediction. The AUCs in the bootstrapped and external validation samples were similar to those obtained in the development sample. The App is user-friendly, requires a minimum amount of information, and provides a risk assessment of low, medium, or high accompanied by advice and website links to government recommendations. Conclusions: Prediction equations for risk of childhood obesity have been developed and incorporated into a novel App, thereby providing proof of concept that childhood obesity prediction research can be integrated with advancements in technology

Influence of muscle mass in the assessment of lower limb strength in COPD: validation of the prediction equation

Absence of established reference values limits application of quadriceps maximal voluntary contraction (QMVC) measurement. The impact of muscle mass inclusion in predictions is unclear. Prediction equations encompassing gender, age and size with (FFM+) and without (FFM−), derived in healthy adults (n=175), are presented and compared in two COPD cohorts recruited from primary care (COPD-PC, n=112) and a complex care COPD clinic (COPD-CC, n=189). Explained variance was comparable between the prediction models (R2: FFM+: 0.59, FFM−: 0.60) as were per cent predictions in COPD-PC (88.8%, 88.3%). However, fat-free mass inclusion reduced the prevalence of weakness in COPD, particularly in COPD-CC where 11.9% fewer were deemed weak

The influence of muscle mass in the assessment of lower limb strength in COPD [Abstract]

The influence of muscle mass in the assessment of lower limb strength in COPD [Abstract

Ethnic differences in risk factors for adverse birth outcomes between Pakistani, Bangladeshi and White British mothers

Aim: Reducing poor maternal and infant outcomes in pregnancy is the aim of maternity care. Adverse health behaviours lead to increased risk and can adversely mediate birth outcomes. This study examines whether risk factors are similar, different or clustered according to maternal ethnicity. Design: Retrospective analysis of routinely collected data (2008-2013) Methods: We analysed data routinely collected data from a local University Hospital Ciconia Maternity information System (CMiS), for White British, Pakistani and Bangladeshi women (N=15,211) using cross-tabulations, ANCOVA, adjusted standardised residuals (ASR) and Pearson Chi-square statistics. Results: The results demonstrate distinct clusters of risk factors between White British, Pakistani and Bangladeshi mothers’. Additionally, Pakistani mothers had the highest number of statistically significant risk factors, according to maternal ethnicity, including showing that 49% of women in this cohort that were diagnosed with diabetes were Pakistani, 21.5% of White British women smoked and results showed that Bangladeshi mothers delivered the lightest weight infants (adjusted mean: 3055.4g). Conclusions: This study found differences in the risk factors between White British, Pakistani and Bangladeshi mothers. The identified risk factors were clustered by maternal ethnicity. Impact: Identification of these risk factor clusters can help policy makers and clinicians direct resources and may help reduce ethnic variation found in these populations that might be attributed to adverse health behaviours and increased risk factors

ATG7 regulates energy metabolism, differentiation and survival of Philadelphia chromosome-positive cells

A major drawback of tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is that primitive CML cells are able to survive TKI-mediated BCR-ABL inhibition, leading to disease persistence in patients. Investigation of strategies aiming to inhibit alternative survival pathways in CML is therefore critical. We have previously shown that a nonspecific pharmacological inhibition of autophagy potentiates TKI-induced death in Philadelphia chromosome-positive cells. Here we provide further understanding of how specific and pharmacological autophagy inhibition affects nonmitochondrial and mitochondrial energy metabolism and reactive oxygen species (ROS)-mediated differentiation of CML cells and highlight ATG7 (a critical component of the LC3 conjugation system) as a potential specific therapeutic target. By combining extra- and intracellular steady state metabolite measurements by liquid chromatography-mass spectrometry with metabolic flux assays using labeled glucose and functional assays, we demonstrate that knockdown of ATG7 results in decreased glycolysis and increased flux of labeled carbons through the mitochondrial tricarboxylic acid cycle. This leads to increased oxidative phosphorylation and mitochondrial ROS accumulation. Furthermore, following ROS accumulation, CML cells, including primary CML CD34+ progenitor cells, differentiate toward the erythroid lineage. Finally, ATG7 knockdown sensitizes CML progenitor cells to TKI-induced death, without affecting survival of normal cells, suggesting that specific inhibitors of ATG7 in combination with TKI would provide a novel therapeutic approach for CML patients exhibiting persistent disease

5-aminosalicylic acid inhibits stem cell function in human adenoma derived cells: Implications for chemoprophylaxis in colorectal tumorigenesis

Background: Most colorectal cancers (CRC) arise sporadically from precursor lesions: colonic polyps. Polyp resection prevents progression to CRC. Risk of future polyps is proportional to the number and size of polyps detected at screening, allowing identification of high-risk individuals who may benefit from effective chemoprophylaxis. We aimed to investigate the potential of 5-aminosalicylic acid (5-ASA), a medication used in the treatment of ulcerative colitis, as a possible preventative agent for sporadic CRC. Methods: Human colorectal adenoma (PC/AA/C1, S/AN/C1 and S/RG/C2), transformed adenoma PC/AA/C1/SB10 and carcinoma cell lines (LS174T and SW620) were treated with 5-ASA. The effect on growth in two- and three-dimensional (3D) culture, β-catenin transcriptional activity and on cancer stemness properties of the cells were investigated. Results: 5-ASA was shown, in vitro, to inhibit the growth of adenoma cells and suppress β-catenin transcriptional activity. Downregulation of β-catenin was found to repress expression of stem cell marker LGR5 (leucine-rich G protein-coupled receptor-5) and functionally suppress stemness in human adenoma and carcinoma cells using 3D models of tumorigenesis. Conclusions: 5-ASA can suppress the cancer stem phenotype in adenoma-derived cells. Affordable and well-tolerated, 5-ASA is an outstanding candidate as a chemoprophylactic medication to reduce the risk of colorectal polyps and CRC in those at high risk