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1.
BJOG ; 131(3): 278-287, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37503769

RESUMO

OBJECTIVE: To investigate the association between preconception maternal retinal arteriolar calibre and fetal growth. DESIGN, SETTING AND POPULATION: A hospital-based, prospective preconception cohort including 369 women with a singleton live birth. METHODS: We collected detailed information on sociodemographic status, pregnancy history and lifestyle, and performed retinal imaging at the preconception visit. MAIN OUTCOME MEASURES: We retrieved medical records documenting fetal growth biometrics (e.g., abdominal circumference [AC], head circumference [HC], femur length [FL]) at 11-13, 18-21, 24-28, and 32-34 weeks throughout pregnancy. We then computed the z scores for all fetal growth biometrics from 14 weeks of gestation where data were available, referencing the INTERGROWTH-21st fetal growth chart. We used a linear mixed model to estimate the association between maternal preconception retinal arteriolar calibre and fetal growth biometrics z scores throughout pregnancy, with random intercept accounting for repeated measures within individuals. We then performed a multivariable linear regression of maternal preconception retinal arteriolar calibre and z score changes for all fetal growth biometrics between 24-28 weeks and 32-34 weeks of gestation, after full adjustment. RESULTS: Maternal preconception generalised retinal arteriolar narrowing was consistently associated with a reduction in fetal AC z scores (-0.34; 95% CI -0.66 to -0.03) throughout pregnancy. In addition, women with preconception generalised retinal arteriolar narrowing tended to have significantly reduced z score changes in AC (-0.41; 95% CI -0.90 to -0.001) and fetal FL (-0.55; 95% CI -1.00 to -0.10) between 24-28 weeks and 32-34 weeks of gestation, respectively. CONCLUSIONS: Our findings suggest that women with narrower preconception retinal arterioles had smaller fetuses, evidenced by reductions in AC and FL z score throughout pregnancy.


Assuntos
Desenvolvimento Fetal , Feto , Gravidez , Feminino , Humanos , Estudos Prospectivos , Idade Gestacional , Biometria , Ultrassonografia Pré-Natal/métodos
2.
BMC Med ; 21(1): 99, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36927416

RESUMO

BACKGROUND: Metabolomic changes during pregnancy have been suggested to underlie the etiology of gestational diabetes mellitus (GDM). However, research on metabolites during preconception is lacking. Therefore, this study aimed to investigate distinctive metabolites during the preconception phase between GDM and non-GDM controls in a nested case-control study in Singapore. METHODS: Within a Singapore preconception cohort, we included 33 Chinese pregnant women diagnosed with GDM according to the IADPSG criteria between 24 and 28 weeks of gestation. We then matched them with 33 non-GDM Chinese women by age and pre-pregnancy body mass index (ppBMI) within the same cohort. We performed a non-targeted metabolomics approach using fasting serum samples collected within 12 months prior to conception. We used generalized linear mixed model to identify metabolites associated with GDM at preconception after adjusting for maternal age and ppBMI. After annotation and multiple testing, we explored the additional predictive value of novel signatures of preconception metabolites in terms of GDM diagnosis. RESULTS: A total of 57 metabolites were significantly associated with GDM, and eight phosphatidylethanolamines were annotated using HMDB. After multiple testing corrections and sensitivity analysis, phosphatidylethanolamines 36:4 (mean difference ß: 0.07; 95% CI: 0.02, 0.11) and 38:6 (ß: 0.06; 0.004, 0.11) remained significantly higher in GDM subjects, compared with non-GDM controls. With all preconception signals of phosphatidylethanolamines in addition to traditional risk factors (e.g., maternal age and ppBMI), the predictive value measured by area under the curve (AUC) increased from 0.620 to 0.843. CONCLUSIONS: Our data identified distinctive signatures of GDM-associated preconception phosphatidylethanolamines, which is of potential value to understand the etiology of GDM as early as in the preconception phase. Future studies with larger sample sizes among alternative populations are warranted to validate the associations of these signatures of metabolites and their predictive value in GDM.


Assuntos
Diabetes Gestacional , Gravidez , Feminino , Humanos , Diabetes Gestacional/diagnóstico , Estudos de Casos e Controles , Fosfatidiletanolaminas , Fatores de Risco , Mães
3.
BMC Med ; 21(1): 472, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-38031185

RESUMO

BACKGROUND: Increasing maternal glycaemia across the continuum during pregnancy may predispose offspring to subsequent cardiometabolic risk later in life. However, evidence of long-term impacts of maternal glycemic status on offspring amino acid (AA) profiles is scarce. We aimed to investigate the association between maternal antenatal glycaemia and offspring mid-childhood amino acid (AA) profiles, which are emerging cardiometabolic biomarkers. METHODS: Data were drawn from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, a multi-ethnic Asian birth cohort. A subset of 422 mother-child dyads from the GUSTO study, who was followed from early pregnancy to mid-childhood, was included. Mothers underwent an oral glucose tolerance test (OGTT) at 26-28 weeks gestation, with fasting and 2-h plasma glucose concentrations measured and gestational diabetes mellitus (GDM) diagnosed per WHO 1999 guidelines. Offspring fasting plasma samples were collected at mean age 6.1 years, from which AA profiles of nine AAs, alanine, glutamine, glycine, histidine, isoleucine, leucine, valine, phenylalanine, and tyrosine were measured. Total branched-chain amino acids (BCAAs) were calculated as the sum of isoleucine, leucine, and valine concentrations. Multi-variable linear regression was used to estimate the association of maternal glycemic status and offspring mid-childhood AA profiles adjusting for maternal age, ethnicity, maternal education, parity, family history of diabetes, ppBMI, child sex, age and BMI z-scores. RESULTS: Approximately 20% of mothers were diagnosed with GDM. Increasing maternal fasting glucose was significantly associated with higher offspring plasma valine and total BCAAs, whereas higher 2-h glucose was significantly associated with higher histidine, isoleucine, valine, and total BCAAs. Offspring born to mothers with GDM had higher valine (standardized mean difference 0.27 SD; 95% CI: 0.01, 0.52), leucine (0.28 SD; 0.02, 0.53), and total BCAAs (0.26 SD; 0.01, 0.52) than their counterparts. Inconsistent associations were found between maternal GDM and other amino acids among offspring during mid-childhood. CONCLUSIONS: Increasing maternal fasting and post-OGTT glucose concentrations at 26-28 weeks gestation were significantly associated with mid-childhood individual and total BCAAs concentrations. The findings suggest that elevated maternal glycaemia throughout pregnancy, especially GDM, may have persistent programming effects on offspring AA metabolism which were strongly associated with adverse cardiometabolic profiles at mid-childhood.


Assuntos
Doenças Cardiovasculares , Diabetes Gestacional , Hiperglicemia , Criança , Humanos , Gravidez , Feminino , Coorte de Nascimento , Leucina , Isoleucina , Histidina , Glucose , Valina , Índice de Massa Corporal
4.
Am J Obstet Gynecol ; 229(6): 617-631, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37506751

RESUMO

OBJECTIVE: We conducted a systematic review and meta-analysis of the effects of Mediterranean diet on female reproductive health outcomes over the life-course. DATA SOURCES: We searched PubMed, Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to identify eligible studies published till February 2022. Eligible references from identified studies and review articles were also considered. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, prospective cohort studies, or nested case-control studies examining Mediterranean diet and major female reproductive outcomes over the lifespan, including clinical outcomes from childhood to adulthood (menarche, polycystic ovary syndrome, endometriosis, and outcomes related to fertility, pregnancy, and menopause), were included for review. METHODS: Two independent reviewers screened and performed data extraction and risk-of-bias assessment. We performed random-effects meta-analysis to obtain summary relative risks and 95% confidence intervals for major female reproductive outcomes. Subgroup analyses were performed for several pregnancy outcomes according to timing of the interventions for randomized controlled trials and timing of the dietary assessment for observational studies. RESULTS: Thirty-two studies (9 randomized controlled trials, 22 prospective cohort studies, and 1 nested case-control study) involving 103,204 predominantly White women (>95%) were included. The pooled relative risk (95% confidence interval) comparing randomization to Mediterranean diet vs a control diet based on 7 randomized controlled trials was 0.74 (0.55-0.99) for gestational diabetes mellitus, 0.45 (0.26-0.76) for preterm birth, 0.71 (0.51-1.00) for gestational hypertension, and 0.82 (0.54-1.22) for preeclampsia; the effect sizes for preterm birth were greater in randomized controlled trials that initiated the interventions in first trimester vs after first trimester (P heterogeneity=.02). We observed inverse associations for all the above-mentioned pregnancy outcomes based on 9 cohort studies. There was suggestive evidence of favorable associations between Mediterranean diet adherence with fertility and gestational weight management. Limited studies suggested associations between higher Mediterranean diet adherence and later time to menarche and fewer vasomotor menopausal symptoms, null associations for polycystic ovary syndrome-like phenotype and pregnancy loss, and positive associations for luteal phase deficiency. CONCLUSION: Adherence to Mediterranean diet may lower risks of adverse pregnancy outcomes among predominantly White populations. For fertility-related outcomes, available evidence supporting potential beneficial effects is suggestive yet limited. For other reproductive outcomes across the lifespan, data remains sparse.


Assuntos
Dieta Mediterrânea , Síndrome do Ovário Policístico , Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Criança , Adolescente , Adulto Jovem , Saúde Reprodutiva , Longevidade , Estudos de Casos e Controles , Estudos Prospectivos
5.
J Org Chem ; 87(10): 6807-6811, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35507767

RESUMO

We report herein the synthesis of 1,3-enynes via palladium-catalyzed cross-coupling between enone derivatives and alkynylsilanes. The employment of an appropriate pyridine-oxazoline ligand is the key to the C-C cleavage and the high E/Z stereoselectivity. This protocol features broad substrate scope and wide functional-group tolerance, affording the desired products in moderate-to-good yields. Late-stage diversification of natural product ß-ionone further demonstrated the synthetic utility of this protocol.


Assuntos
Paládio , Catálise , Ligantes , Paládio/química
6.
Am J Epidemiol ; 190(7): 1414-1423, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33565574

RESUMO

Observational studies reporting on adjusted associations between childhood body mass index (BMI; weight (kg)/height (m)2) rebound and subsequent cardiometabolic outcomes have often not paid explicit attention to causal inference, including definition of a target causal effect and assumptions for unbiased estimation of that effect. Using data from 649 children in a Boston, Massachusetts-area cohort recruited in 1999-2002, we considered effects of stochastic interventions on a chosen subset of modifiable yet unmeasured exposures expected to be associated with early (

Assuntos
Algoritmos , Índice de Massa Corporal , Causalidade , Funções Verossimilhança , Estudos Observacionais como Assunto/métodos , Adolescente , Boston , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Processos Estocásticos
7.
Hum Reprod ; 36(11): 2935-2947, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34492112

RESUMO

STUDY QUESTION: Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER: In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY: Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION: A total of 652 women of Chinese, Malay or Indian ethnicity 18-45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant's pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE: Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51-0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55-0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56-1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S): This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03531658.


Assuntos
Etnicidade , Tempo para Engravidar , Criança , Feminino , Humanos , Microcirculação , Microvasos , Gravidez , Estudos Prospectivos , Singapura/epidemiologia
8.
J Org Chem ; 85(6): 4475-4481, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077291

RESUMO

Here, we report O-methyl S-aryl thiocarbonates as a versatile esterification reagent for palladium-catalyzed methoxycarbonylation of arylboronic acid in the presence of copper(I) thiophene-2-carboxylate (CuTC). The reaction condition is mild, and a variety of substituents including sensitive -Cl, -Br, and free -NH2 could be tolerated. Further applications in the late-stage esterification of some pharmaceutical drugs demonstrate the broad utility of this method.

9.
Angew Chem Int Ed Engl ; 59(34): 14388-14393, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32463551

RESUMO

The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of aryl ketones in an analogous manner via carbon-carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of aryl ketones. An exploratory study of this approach is typically based on carbon-carbon cleavage triggered by ring-strain release and chelation assistance, and the products are also limited to a specific structural motif. Here we report a ligand-promoted ß-carbon elimination strategy to activate the carbon-carbon bonds, which results in a range of transformations of aryl ketones, leading to useful aryl borates, and also to biaryls, aryl nitriles, and aryl alkenes. The use of a pyridine-oxazoline ligand is crucial for this catalytic transformation. A gram-scale borylation reaction of an aryl ketone via a simple one-pot operation is reported. The potential utility of this strategy is also demonstrated by the late-stage diversification of drug molecules probenecid, adapalene, and desoxyestrone, the fragrance tonalid as well as the natural product apocynin.

10.
Am J Epidemiol ; 188(11): 1913-1922, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497850

RESUMO

Childhood blood pressure (BP) is a strong predictor of later risk of cardiovascular disease. However, few studies have assessed dynamic BP trajectories throughout the early-life period. We investigated the relationship between early-life factors and systolic BP (SBP) from infancy to adolescence using linear spline mixed-effects models among 1,370 children from Project Viva, a Boston, Massachusetts-area cohort recruited in 1999-2002. After adjusting for confounders and child height, we observed higher SBP in children exposed to gestational diabetes mellitus (vs. normoglycemia; age 3 years: ß = 3.16 mm Hg (95% confidence interval (CI): 0.28, 6.04); age 6 years: ß = 1.83 mm Hg (95% CI: 0.06, 3.60)), hypertensive disorders of pregnancy (vs. normal maternal BP; age 6 years: ß = 1.39 mm Hg (95% CI: 0.10, 2.67); age 9 years: ß = 1.84 mm Hg (95% CI: 0.34, 3.34); age 12 years: ß = 1.70 mm Hg (95% CI: 0.48, 2.92)), higher neonatal SBP (per 10-mm Hg increase; age 3 years: ß = 1.26 mm Hg (95% CI: 0.42, 2.09); age 6 years: ß = 1.00 mm Hg (95% CI: 0.49, 1.51); age 9 years: ß = 0.75 mm Hg (95% CI: 0.17, 1.33)), and formula milk in the first 6 months of life (vs. breast milk only; age 12 years: ß = 2.10 mm Hg (95% CI: 0.46, 3.74); age 15 years: ß = 3.52 mm Hg (95% CI: 1.40, 5.64); age 18 years: ß = 4.94 mm Hg (95% CI: 1.88, 7.99)). Our findings provide evidence of programming of offspring SBP trajectories by gestational diabetes, hypertensive disorders of pregnancy, and formula milk intake and of neonatal BP being a potentially useful marker of childhood BP. These factors could be relevant in identifying children who are at risk of developing elevated BP.


Assuntos
Pressão Sanguínea , Efeitos Tardios da Exposição Pré-Natal , Adulto , Criança , Pré-Escolar , Diabetes Gestacional , Feminino , Humanos , Hipertensão Induzida pela Gravidez , Lactente , Recém-Nascido , Masculino , Gravidez
11.
J Pediatr ; 215: 123-131.e2, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31604633

RESUMO

OBJECTIVE: To investigate the association of preconception parental obesity (body mass index [BMI] ≥30 kg/m2) with offspring pubertal development. STUDY DESIGN: Among 1377 children from a prospective prebirth cohort in Boston, we examined markers of puberty (age at peak height velocity [PHV], age at menarche, self-reported pubertal development score), and adrenarche (pictograph Tanner pubic hair staging). We used multivariable regression models to examine associations of maternal and paternal obesity with offspring pubertal indices, and applied marginal structural models to estimate the controlled direct effect not mediated by offspring prepubertal BMI. RESULTS: The prevalence of paternal obesity alone, maternal obesity alone, and biparental obesity were 10.5%, 10.1%, and 5%, respectively. After adjusting for demographic and socioeconomic factors, parental heights and maternal age at menarche, maternal obesity alone (vs neither parent with obesity) was associated with earlier age at PHV (ß -0.30 years; 95% CI -0.57, -0.03) and higher early adolescent pubertal score (0.29 units; 0.10, 0.48) in boys, but not with pubertal or adrenarchal outcomes in girls. Paternal obesity alone was not associated with any outcomes in either boys or girls. Biparental obesity was associated with earlier age at PHV in boys and earlier menarche in girls. Using marginal structural models with stabilized inverse probability weighting, maternal obesity alone had significant controlled direct effects on age at PHV (-0.31 years; -0.62, 0.00) and on pubertal score (0.22 units; 0.00, 0.44) in boys, independent of prepubertal BMI. CONCLUSION: Maternal, but not paternal, obesity is associated with earlier pubertal development in boys, and such association is independent of prepubertal BMI.


Assuntos
Deficiências do Desenvolvimento/etiologia , Menarca/fisiologia , Obesidade/epidemiologia , Pais , Maturidade Sexual/fisiologia , Adolescente , Adulto , Fatores Etários , Índice de Massa Corporal , Boston/epidemiologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Idade Materna , Obesidade/complicações , Prevalência , Estudos Prospectivos
12.
BJOG ; 131(7): 1020-1021, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38342607
13.
J Pediatr ; 201: 69-77.e8, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29960766

RESUMO

OBJECTIVE: To assess associations of pre-, perinatal, and parental factors with age and magnitude at body mass index (BMI) peak and rebound. STUDY DESIGN: Among 1681 children with BMI data from birth to mid-childhood in Project Viva, we fitted individual BMI trajectories using mixed-effect models with natural cubic spline functions and estimated age and magnitude at peak in infancy and rebound in early childhood. We used stepwise multivariable regression to identify predictors of peak and rebound in the 1354 (63.6%) children with estimable trajectory milestones. RESULTS: The mean (SD) of age at BMI peak was 8.4 (2.7) months and at rebound was 59.8 (19.6) months, and the mean (SD) of magnitude at peak was 18.0 (1.4) kg/m2 and at rebound was 15.9 (1.2) kg/m2. Girls had a later age at peak, earlier age at rebound, and lower magnitudes at peak and rebound than boys. Maternal isolated hyperglycemia (vs normoglycemia: ß 0.7 months [95% CI 0.2-1.2]) and pre-eclampsia (vs normal blood pressure: 1.6 months [0.8-2.4]) were associated with a later peak, and impaired glucose tolerance (vs normoglycemia: -0.5 kg/m2 [-0.9, -0.1]) was associated with a lower magnitude at peak. Greater maternal first-trimester weight gain, smoking during pregnancy, no breastfeeding, parental obesity, and no university education were associated with greater BMI at rebound. CONCLUSIONS: We have identified modifiable prenatal and parental predictors of BMI peak in infancy and rebound in childhood. Early-life interventions that address these factors may be effective in changing BMI peak and rebound and potentially preventing later obesity.


Assuntos
Índice de Massa Corporal , Desenvolvimento Infantil , Obesidade Infantil , Adulto , Pré-Escolar , Estudos de Coortes , Escolaridade , Feminino , Ganho de Peso na Gestação , Intolerância à Glucose/epidemiologia , Humanos , Hiperglicemia/epidemiologia , Lactente , Estudos Longitudinais , Masculino , Massachusetts/epidemiologia , Obesidade/epidemiologia , Pais , Pré-Eclâmpsia/epidemiologia , Gravidez , Primeiro Trimestre da Gravidez , Fatores de Risco , Fumar/efeitos adversos
14.
Diabetologia ; 60(12): 2368-2376, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28939944

RESUMO

AIMS/HYPOTHESIS: Changes in retinal microvasculature may reflect insulin resistance. We examined the association of changes in retinal microvasculature during pregnancy and risk of subsequent abnormal glucose metabolism in a cohort of mothers at baseline and 5 years postpartum. METHODS: Of the participants from the Singapore birth cohort (Growing Up in Singapore Towards Healthy Outcomes [GUSTO]), 276 mothers attended both baseline (at 26-28 weeks of gestation) and follow-up (5 year postpartum) visits. At baseline we performed retinal photography and assessed retinal microvascular variables using a validated grading system. At follow-up, we assessed glucose tolerance using a 75 g OGTT. We defined abnormal glucose metabolism if participants: (1) had onset of gestational diabetes mellitus (GDM) in subsequent pregnancies within a 5 year follow-up period (n = 103) or (2) had prediabetes (impaired fasting glucose, impaired glucose tolerance or HbA1c 5.7-6.4% [39-46 mmol/mol]) and diabetes diagnosed at the 5 year follow-up visit (n = 84), according to WHO guidelines. RESULTS: The incidence of GDM in subsequent pregnancy and abnormal glucose metabolism 5 years postpartum was 25.2% and 30.4%, respectively. Each 10 µm widening in retinal venular calibre was associated with a significant risk of postpartum abnormal glucose metabolism (RR 1.2 [95% CI 1.0, 1.5]), independent of maternal age, college education, ethnicity, pre-pregnancy BMI and GDM at baseline. Narrower retinal arteriolar calibre and venular branching angle at baseline was associated with a higher insulin resistance index (1.4 [95% CI 1.1, 1.7] and 1.3 [95% CI 1.1, 1.6], respectively) at follow-up. CONCLUSIONS/INTERPRETATION: Retinal microvasculature in pregnant women was associated with abnormal glucose metabolism 5 years postpartum. Alteration of microvascular structure during pregnancy may signal subclinical changes that underlie the development of prediabetes and diabetes.


Assuntos
Diabetes Gestacional/metabolismo , Estado Pré-Diabético/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Gestacional/fisiopatologia , Feminino , Intolerância à Glucose/metabolismo , Intolerância à Glucose/fisiopatologia , Teste de Tolerância a Glucose , Hemoglobinas Glicadas/metabolismo , Humanos , Microvasos/metabolismo , Microvasos/fisiopatologia , Período Pós-Parto , Estado Pré-Diabético/fisiopatologia , Gravidez , Retina/metabolismo , Retina/fisiopatologia
15.
Microcirculation ; 24(2)2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27749000

RESUMO

OBJECTIVE: Type 1 diabetes mellitus (T1DM) is a major disease affecting a large number of young patients. In the recent years, retinal vascular imaging has provided an objective assessment of vascular health in patients with T1DM. Our study aimed to review the current literature on retinal vascular parameters in young patients with T1DM in order to understand the following: (i) How retinal vessels are affected in T1DM (ii) How such vascular changes can be predictive of future diabetic microvascular complications METHODS: We performed a systematic review and extracted relevant data from 17 articles. RESULTS: We found significant correlations between retinal vessel changes and diabetes-related risk factors (eg, hypertension, hyperlipidemia, and obesity), diabetes-related features (eg, diabetes duration and glycemic control), and diabetes-related microvascular complications (eg, diabetic retinopathy, nephropathy, and neuropathy). CONCLUSION: Our findings suggest that retinal microvasculature is associated with both disease severity and complications in young patients with T1DM.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Retinopatia Diabética/diagnóstico por imagem , Humanos , Microvasos/diagnóstico por imagem , Microvasos/patologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Fatores de Risco
16.
BMC Ophthalmol ; 17(1): 60, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28615013

RESUMO

BACKGROUND: Poor glycemic control in Type 1 Diabetes (T1D) patients is strongly associated with an increased risk of diabetes-related microvascular complications later in life, but it is unclear whether short period of poor glycemic control in children with T1D can cause evident microvascular morphological changes long before any pathological manifestation. Our study aimed to investigate the longitudinal association between poor glycemic control and subsequent changes in retinal microvasculature, in a pilot study of 55 pediatric T1D patients from Singapore after a one-year follow-up. METHODS: This is a hospital-based, exposure-matched and retrospective longitudinal study. A total of 55 T1D patients were included from Singapore KK Women's and Children Hospital, 28 of whom had poor glycemic control (average glycated hemoglobin [HbA1c] ≥8% during the year) while the other 27 age- and gender-matched subjects had good glycemic control (HbA1c <8%). Retinal photography was taken at diabetes annual screening and images were graded by trained graders using a semi-automated computer-based program (Singapore I Vessel Assessment [SIVA], version 4.0, Singapore Eye Research Institute, Singapore) and a spectrum of retinal vascular parameters (e.g. caliber, tortuosity, branching angle and fractal dimension) were measured quantitatively from 0.5 to 2.0 disc diameters. RESULTS: There was no significant difference in ethnicity, duration of T1D, blood pressure, body mass index (BMI) and low-density cholesterol lipoprotein (LDL) between the two groups. Retinal imaging was obtained at the end of 1 year of glycemic control assessment. In multiple linear regression adjusting for ethnicity, BMI, LDL and duration of T1D, patients with poor glycemic control tended to have marginally wider retinal arteriolar caliber (6.0 µm, 95% CI: -0.9, 12.8) and had significantly larger retinal arteriolar branching angle (10.1 degrees, 95% CI: 1.4, 18.9) compared with their age- and gender- matched counterparts with good glycemic control. CONCLUSIONS: Our findings showed that abnormal retinal microvascular morphology was evident in pediatric patients with T1D after one-year's poor glycemic control. Such morphological abnormalities may lead to future development of microvascular complications among T1D pediatric patients with poor glycemic control.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/complicações , Retinopatia Diabética/diagnóstico , Microvasos/patologia , Vasos Retinianos/patologia , Medição de Risco , Adolescente , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/etiologia , Feminino , Seguimentos , Hemoglobinas Glicadas/metabolismo , Humanos , Incidência , Masculino , Projetos Piloto , Estudos Retrospectivos , Fatores de Risco , Singapura/epidemiologia , Fatores de Tempo
17.
BMC Ophthalmol ; 17(1): 4, 2017 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-28100181

RESUMO

BACKGROUND: Small-vessel dysfunction may be an important consequence of chronic hyperglycemia. We examined the association between gestational diabetes mellitus (GDM), a state of transient hyperglycemia during pregnancy, and retinal microvascular changes in pregnant women at 26-28 weeks of pregnancy. METHODS: A total of 1136 pregnant women with singleton pregnancies were recruited during their first trimester at two major Singapore maternity hospitals in an on-going birth cohort study. Participants underwent an oral glucose tolerance test and retinal imaging at 26-28 weeks gestation (n = 542). We used the 1999 World Health Organization (WHO) criteria to define GDM: ≥7.0 mmol/L for fasting glucose and/or ≥7.8 mmol/L for 2-h post-glucose. Retinal microvasculature was measured using computer software (Singapore I Vessel Analyzer, SIVA version 3.0, Singapore Eye Research Institute, Singapore) from the retinal photographs. RESULTS: In a multiple linear regression model adjusting for age, ethnicity and maternal education, mothers with GDM had narrower arteriolar caliber (-1.6 µm; 95% Confidence Interval [CI]: -3.1 µm, -0.2 µm), reduced arteriolar fractal dimension (-0.01 Df; 95% CI: -0.02 Df, -0.001 Df;), and larger arteriolar branching angle (1.8°; 95% CI: 0.3°, 3.3°) than mothers without GDM. After further adjusting for traditional risks of GDM, arteriolar branching angle remained significantly larger in mothers with GDM than those without GDM (2.0°; 95% CI: 0.5°, 3.6°). CONCLUSIONS: GDM was associated with a series of retinal arteriolar abnormalities, including narrower caliber, reduced fractal dimension and larger branching angle, suggesting that transient hyperglycemia during pregnancy may cause small-vessel dysfunction.


Assuntos
Diabetes Gestacional/fisiopatologia , Microvasos/fisiologia , Vasos Retinianos/fisiopatologia , Adulto , Feminino , Humanos , Hiperglicemia/fisiopatologia , Microcirculação/fisiologia , Gravidez , Segundo Trimestre da Gravidez/fisiologia , Análise de Regressão , Singapura , Adulto Jovem
18.
J Physiol ; 594(8): 2175-203, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26435039

RESUMO

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent years, studies have shown that the origins of CVD may be traced to vascular and metabolic processes in early life. Retinal vascular imaging is a new technology that allows detailed non-invasive in vivo assessment and monitoring of the microvasculature. In this systematic review, we described the application of retinal vascular imaging in children and adolescents, and we examined the use of retinal vascular imaging in understanding CVD risk in early life. We reviewed all publications with quantitative retinal vascular assessment in two databases: PubMed and Scopus. Early life CVD risk factors were classified into four groups: birth risk factors, environmental risk factors, systemic risk factors and conditions linked to future CVD development. Retinal vascular changes were associated with lower birth weight, shorter gestational age, low-fibre and high-sugar diet, lesser physical activity, parental hypertension history, childhood hypertension, childhood overweight/obesity, childhood depression/anxiety and childhood type 1 diabetes mellitus. In summary, there is increasing evidence supporting the view that structural changes in the retinal microvasculature are associated with CVD risk factors in early life. Thus, the retina is a useful site for pre-clinical assessment of microvascular processes that may underlie the future development of CVD in adulthood.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Metabólicas/epidemiologia , Doenças Retinianas/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem , Adolescente , Peso ao Nascer , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/complicações , Doenças Retinianas/epidemiologia , Doenças Retinianas/etiologia , Vasos Retinianos/crescimento & desenvolvimento
19.
Anticancer Drugs ; 27(10): 979-87, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27548349

RESUMO

Worldwide, cervix carcinoma is among the most dangerous cancer types, and novel therapies are under development. Cancer treatments are often hampered because of lack of specificity. The chicken anemia virus-derived apoptin induces apoptosis selectively in tumor cells and leaves normal cells unharmed. Here, we have carried out in-vitro and in-vivo studies on the cytotoxic effect of apoptin in a cervix carcinoma model. Apoptin was fused to the protein transduction domain 4 (PTD4), enabling delivery of the fusion protein across cellular membranes. PTD4-apoptin protein is located in the nuclei of human cervical carcinoma HeLa cells and in the cytoplasm of normal cells L02. By MTT and flow cytometry analysis, we have proven that PTD4-apoptin protein induced apoptosis in the cervical carcinoma cells. PTD4-apoptin enhanced the level of active executioner caspase-3. Neither caspase-3 activation nor apoptin-induced accumulation of the mitochondrial outer-membrane protein Mfn-2 was affected by ectopic Bcl-2 expression. In contrast, apoptin-mediated AKT activation was inhibited by Bcl-2. In vivo, cervix carcinoma xenografts were treated for 7 days with PTD4-apoptin protein. The PTD4-apoptin treatment induced a decrease in the cervix carcinoma, whereas the PTD4-GFP protein-treated controls expanded significantly. TUNEL analysis showed that PTD4-apoptin protein induced apoptosis in cervix carcinoma cells, in contrast to the control PTD-GFP-treated ones. Our results indicate that apoptin is a potential anticancer agent for treating cervix carcinoma.


Assuntos
Proteínas Recombinantes de Fusão/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Distribuição Aleatória , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Asian Nat Prod Res ; 18(11): 1079-90, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27314303

RESUMO

5,6-Dihydroxy-3,7,4'-trimethoxyflavonol (AH5), 5,6,3'-trihydroxy-3,7,4'-trimethoxyflavonol (AH22), artemetin, and oroxylin A are four flavonoids with the same 2-phenyl-chromone skeleton isolated from the Chinese herb Aster himalaicus. The aim of this study was to evaluate the structure-activity relationship of these four analogs and the mediation of AH5 cytotoxicity via G2/M arrest and apoptosis in human hepatocellular carcinoma (HCC) cells. 3-(4,5-Dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated AH5 showed the better potency to inhibit proliferation in human HCC cells, which suggested hydroxyl binding to C6 is necessary to anticancer properties, whereas binding to C3' attenuated the activities and increased toxicity in tested cells. Flow cytometry analysis revealed that AH5-induced G2/M arrest and significantly apoptosis in these cell lines. HepG-2 cells were used to further evaluate the antitumor effects and mechanisms of AH5. AH5-induced apoptosis was further confirmed by 4',6-diamidino-2-phenylindole (DAPI) staining and the increased ratio of Bax/Bcl-2. Moreover, AH5 induced the release of cytochrome C and the activation of caspase-9 and caspase-3, thus suggesting mitochondria activation might be involved. Western blot showed that AH5 induced the phosphorylation of Cdc2 and decreased the level of Cyclin B1. These results demonstrated that AH5 could be a proapoptotic leading compound for developing novel anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Flavonóis/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Ciclina B1/metabolismo , Citocromos c/metabolismo , Desenho de Fármacos , Flavonoides/química , Flavonóis/química , Células Hep G2/efeitos dos fármacos , Humanos , Indóis/química , Neoplasias Hepáticas/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estrutura Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade
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