ORCID Profile
0000-0001-6226-8270
Current Organisations
The University of Edinburgh
,
NHS Lothian
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Publisher: Springer Science and Business Media LLC
Date: 24-01-2011
Abstract: Increasing numbers of people are developing type 2 diabetes mellitus, but interventions to prevent and treat the classic microvascular and macrovascular complications have improved, so that people are living longer with the condition. This trend means that novel complications of type 2 diabetes mellitus, which are not targeted by current management strategies, could start to emerge. Cognitive impairment and dementia could come into this category. Type 2 diabetes mellitus is associated with a 1.5-2.5-fold increased risk of dementia. The etiology of dementia and cognitive impairment in people with type 2 diabetes mellitus is probably multifactorial. Chronic hyperglycemia is implicated, perhaps by promoting the development of cerebral microvascular disease. Data suggest that the brains of older people with type 2 diabetes mellitus might be vulnerable to the effects of recurrent, severe hypoglycemia. Other possible moderators of cognitive function include inflammatory mediators, rheological factors and dysregulation of the hypothalamic-pituitary-adrenal axis. Cognitive function should now be included as a standard end point in randomized trials of therapeutic interventions in patients with type 2 diabetes mellitus.
Publisher: Cambridge University Press (CUP)
Date: 21-04-2022
DOI: 10.1017/S2040174422000186
Abstract: Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2 Gen2) at 18 years HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant’s fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.
Publisher: Wiley
Date: 23-04-2012
DOI: 10.1111/J.1365-2265.2011.04317.X
Abstract: Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-ecl sia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-ecl sia. Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic. Severely obese (body mass index, BMI > 40 kg/m(2), n = 194) and lean (BMI < 25 kg/m(2), n = 78) pregnant women. A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma s les at 16, 28 and 36 weeks gestation. Pre-ecl sia, defined using International Society for the Study of Hypertension in Pregnancy guidelines blood pressure delivery gestation birthweight. Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0.001), and in women who later developed pre-ecl sia (P < 0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-ecl sia, area under the receiver-operator characteristic curve was 0.80 (P < 0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0.05) and birthweight (P < 0.0001), and negatively with 28- and 36-week blood pressure (P < 0.0001). Kisspeptin concentration in early pregnancy is a promising biomarker for pre-ecl sia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers.
Publisher: Springer Science and Business Media LLC
Date: 06-2017
DOI: 10.1007/S10555-017-9671-3
Abstract: The significant role of platelets in the protection of tumour cells from immune attack and shear forces and the promotion of tumour cell extravasation from the bloodstream in the process of haematogenous metastasis have been extensively studied. The role of platelets, and in particular platelet membranes, in the promotion of a more metastatic phenotype in tumour cells is a more recent and, therefore, less well-recognised area of research. This review article summarises studies that have focused on the impact of tumour cell interactions with platelets and platelet membranes on tumour cell behaviour in vitro and in vivo. Furthermore, the gene expression changes that occur within tumour cells following contact with platelet membranes are also extensively reviewed. Overall, the interaction of platelet membranes with tumour cells results in a more invasive phenotype and the promotion of epithelial to mesenchymal transition with our own genetic studies revealing that matrix metalloproteinase-1, plasminogen activator inhibitor-1 and interleukin-8 are globally upregulated in a range of tumour cell lines.
Publisher: BMJ
Date: 07-03-2022
DOI: 10.1136/ARCHDISCHILD-2021-321593
Abstract: To determine if preterm birth is associated with adaptation of the hypothalamic–pituitary–adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at weeks or very preterm birth at 28–32 weeks gestation). This study reports findings from a prospective birth cohort. Saliva cortisol concentrations were measured prevaccination and postvaccination, and in the morning and evening, at 4 months chronological age. Infants born at a single Scottish hospital. 45 term-born, 42 very preterm and 16 extremely preterm infants. Cortisol stress response to vaccination (postvaccination minus prevaccination cortisol concentrations), diurnal slope (log-transformed morning minus log-transformed evening cortisol values) and mean log-transformed daily cortisol. Compared with infants born at term, infants born extremely preterm had a blunted cortisol response to vaccination (5.8 nmol/L vs 13.1 nmol/L, difference in means: −7.3 nmol/L, 95% CI −14.0 to −0.6) and a flattened diurnal slope (difference in geometric means: −72.9%, 95% CI −87.1 to −42.8). In contrast, the cortisol response to vaccination (difference in means −2.7 nmol/L, 95% CI −7.4 to 2.0) and diurnal slope at 4 months (difference in geometric means: −33.6%, 95% CI −62.0 to 16.0) did not differ significantly in infants born very preterm compared with infants born at term. Infants born extremely preterm have blunted cortisol reactivity and a flattened diurnal slope. These patterns of HPA axis regulation are commonly seen after childhood adversity and could contribute to later metabolic and neurodevelopmental phenotypes observed in this population.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2017
DOI: 10.1038/IJO.2017.248
Publisher: Springer Science and Business Media LLC
Date: 28-09-2016
DOI: 10.1038/NATURE19806
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.PSYNEUEN.2015.09.019
Abstract: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.PSYNEUEN.2015.05.004
Abstract: Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental s les from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood.
Publisher: American Diabetes Association
Date: 13-11-2013
DOI: 10.2337/DC13-0863
Abstract: Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleep-disordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary, behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized that sleep disorder might increase the risk of hypoglycemia through effects on self-management and glucose regulation. People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing, daytime sleepiness, and occurrence of severe hypoglycemia. Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis including the variables age, sex, duration of diabetes, HbA1c, BMI, and treatment type. Daytime sleepiness may be a novel risk factor for hypoglycemia.
Publisher: The Endocrine Society
Date: 17-05-2021
Abstract: Human and animal studies suggest that hypothalamic-pituitary-adrenal axis (HPA-A) function may be programmed in utero however, these findings are inconsistent. Given the powerful metabolic actions of cortisol, it is important to clarify the influence of early life on adult HPA-A function. To determine the relationship between fetal growth and HPA-A stress response to a psychosocial stressor in young adults. Multigenerational, prospective cohort study (the Raine Study) conducted between 1989 and 1991. King Edward Memorial Hospital, Perth, Western Australia, Australia. A total of 917 participants aged 18 years from Gen2 of the Raine Study. Measures of hypothalamic-pituitary-adrenal axis function before and after exposure to the Trier Social Stress Test. In fully adjusted models, an inverse linear relationship was observed between birthweight and plasma measures of (1) baseline cortisol (β = -0.90%, 95% CI: -1.73 to -0.07 P = 0.03) (2) peak cortisol (β = -0.78%, 95% CI -1.51 to -0.06 P = 0.03) (3) area under the curve with respect to ground (β = -0.89%, 95% CI -1.60 to -0.18 P = 0.01) and (4) adrenal sensitivity (β = -1.02, 95% CI: -1.85 to -0.18 P = 0.02). Similar results were demonstrated for percent optimal birthweight. No consistent quadratic relationships were identified. No associations were found between measures of fetal adiposity and HPA-A function at age 18 years, or fetal growth and HPA-A response pattern. Removal of anticipatory responders from the models substantially attenuated the observed relationships. We observed an inverse linear relationship between fetal growth and HPA-A function at age 18 years. This differs from the inverse parabolic relationship (inverted U curve) reported in adults of advanced age. Altered adrenal sensitivity may underlie this relationship.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.PREGHY.2014.03.028
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis is important for fetal growth and timing of parturition. Maternal obesity is associated with macrosomia (birthweight ⩾4000g) and prolonged pregnancy (⩾41weeks). We aimed to characterise HPA axis hormones in obese pregnancy and to test associations with these pregnancy outcomes. Fasting cortisol was measured by radioimmunoassay in venous blood at 16, 28 and 36 weeks of gestation in 286 obese (BMI 44.05±3.98kg/m(2)) and 137 lean (BMI 22.71±1.66kg/m(2)) pregnant women. In subsets (n=20 obese, 20 lean) we measured corticosteroid binding globulin (CBG) and CRH by radioimmunoassay progesterone, estradiol (E2), estriol (E3) and sex-hormone-binding-globulin (SHBG) by ELISA and albumin by bromocresol green binding. Free cortisol levels were calculated using Coolen's equation. Cortisol, CBG, calculated free cortisol, CRH, E2, E3, progesterone and SHBG levels rose similarly during pregnancy in obese and lean, but were significantly lower in obese (p<0.05). In obese, lower free cortisol at 16 weeks was associated with higher birthweight (r=-0.46, p<0.05). Cortisol was not associated with labour onset. CRH was significantly lower at 36 weeks in women who delivered at ⩾41weeks and in women with macrosomic babies (p<0.05) and correlated negatively with gestation at delivery in obese (r=-0.557, p<0.05). Our findings suggest that decreased HPA axis activity in obese pregnancy may be a mechanism underlying macrosomia and prolonged pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2023
Publisher: Public Library of Science (PLoS)
Date: 10-07-2014
Publisher: F1000 Research Ltd
Date: 16-07-2021
DOI: 10.12688/WELLCOMEOPENRES.15538.2
Abstract: STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables physical measures questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder laboratory s les cognitive tests and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures relevant to the study of depression, psychological resilience, and cognition. In addition, routinely collected historic NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.
Publisher: Cambridge University Press (CUP)
Date: 08-10-2018
DOI: 10.1017/S003329171800291X
Abstract: The prevalence of sleep problems among pregnant women is over 50%, and daytime sleepiness is among the most common sleep problems. Previous studies have associated antenatal sleep problems with adverse maternal health and neonatal outcomes, but the consequences of antenatal sleep problems and particularly daytime sleepiness on child psychological development have not been assessed prospectively. In this prospective cohort study including 111 mother-child dyads, we examined the associations of maternal daytime sleepiness during pregnancy, assessed at 17 and 28 weeks of gestation using the Epworth Sleepiness Scale, with child neuropsychiatric problems and neuropsychological development, assessed with mother-rated questionnaires and in idually administered neuropsychological tests, at child age 2.6–5.7 years (mean = 4.3 years). Independently of sociodemographic and perinatal covariates and maternal depressive and anxiety symptoms during and/or after pregnancy, maternal antenatal daytime sleepiness was associated with increased total [unstandardized regression coefficient ( B ) = 0.25 standard deviation ( s.d. ) units 95% confidence interval (CI) 0.01–0.48] and internalizing ( B = 0.25 s.d. s: 95% CI 0.01–0.49) psychiatric problems and ADHD symptoms ( B = 0.27 s.d. s: 95% CI 0.04–0.50) in children, and with poorer executive function, particularly in the areas of attention, working memory and inhibitory control ( B = −0.39 s.d. s: 95% CI −0.69 to −0.10). Maternal antenatal daytime sleepiness carries adverse consequences for offspring psychological development. The assessment of sleep problems may be an important addition to standard antenatal care.
Publisher: Wiley
Date: 06-07-2009
DOI: 10.1002/PD.2328
Abstract: To investigate whether pregnancies with development of subsequent pre-ecl sia and intra-uterine growth restriction are associated with altered levels of kisspeptin in maternal serum in the second trimester. Retrospective case-control study of 16-20 week serum s les matched for duration of storage at -70 degrees C. Levels of kisspeptin were measured in serum from women with pregnancies with subsequent development of pre-ecl sia (n = 57), intra-uterine growth restriction (n = 118), and matched controls (n = 317). Serum kisspeptin levels were significantly lower in those women who subsequently developed pre-ecl sia than in controls [median (quartile range) 1109 (449) vs 1188 (365) pg/mL, p = 0.029] and in those with intra-uterine growth restriction [1164 (386) vs 1188 (365) pg/mL, p = 0.016]. Kisspeptin levels are lower in maternal serum in the second trimester, in pregnancies associated with placental dysfunction. The differences in kisspeptin are modest, so although not forming a single screening marker in pre-ecl sia and intra-uterine growth restriction, measurement of kisspeptin may be useful in combination with other markers. Understanding the role of kisspeptin in the establishment of the placenta may further our knowledge of the mechanisms underlying placental function.
Publisher: American Diabetes Association
Date: 03-12-2009
DOI: 10.2337/DB09-1163
Abstract: To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes. A cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary–based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood s le at the time of cognitive testing. Higher IL-6 and TNF-α levels were associated with poorer age- and sex-adjusted scores on the majority of the in idual cognitive tests. They were also associated with g using standardized regression coefficients −0.074 to −0.173 (P & 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, IL-6 remained associated with three of the cognitive tests and with g. In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline.
Publisher: F1000 Research Ltd
Date: 25-02-2017
DOI: 10.12688/WELLCOMEOPENRES.15661.1
Abstract: Background: Antenatal corticosteroid treatment (ACT) has been widely accepted as a safe, beneficial treatment which improves outcomes following preterm birth. It has been shown to reduce respiratory distress syndrome and neonatal mortality and is commonly used in threatened or planned preterm delivery, as well as prior to elective Caesarean-section at term. There are some concerns however, that in some cases, ACT is used in patients where clinical benefit has not been established, or may potentially increase harm. Many women who receive ACT do not deliver preterm and the long-term consequences of ACT treatment are unclear. This study aims to evaluate the benefits and harms of ACT using latest trial evidence to allow refinement of current practice. Methods: This study will compare ACT with placebo or non-treatment. Inclusion criteria are: Randomised Controlled Trials (RCT) comparing ACT vs. no ACT (with or without placebo) in all settings. Exclusion criteria are: non-randomised or quasi-randomised studies and studies comparing single vs. multiple courses of ACT. Main outcomes are to evaluate, for women at risk of preterm birth or undergoing planned Caesarean- section, the benefits and harms of ACT, on maternal, fetal, newborn, and long-term offspring health outcomes. The in idual participant data (IPD) of identified RCTs will be collected and consecutively synthesised using meta-analysis with both a one-stage model where all IPD is analysed together and a two-stage model where treatment effect estimates are calculated for each trial in idually first and thereafter pooled in a meta-analysis. Sub-group analysis will be performed to identify heterogeneous effects of ACT across predefined risk groups. Discussion: Co-opt is the Consortium for the Study of Pregnancy Treatments and aims to complete a robust evaluation of the benefits and harms of ACT. This IPD meta-analysis will contribute to this by allowing detailed interrogation of existing trial datasets. PROSPERO registration: CRD42020167312 (03/02/2020)
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Rebecca M Reynolds.