Publications
243 results found
Kindinger L, MacIntyre D, Lees Y, et al., 2016, The impact of progesterone on the vaginal microbiome in high-risk pregnancy with a short cervix, British Maternal & Fetal Medicine Society (BMFMS) 18th Annual Conference 2016, Publisher: Wiley, Pages: 72-72, ISSN: 1471-0528
Cacciatore S, Georgakopoulou N, Jimenez B, et al., 2016, Urine Metabolic Phenotype Diversity in Pregnancy and Its Association with Preterm Delivery and Cervical Length, 63rd Annual Scientific Meeting of the Society for Reproductive Investigation, Publisher: SAGE Publications, Pages: 191A-191A, ISSN: 1933-7205
Migale R, MacIntyre DA, Cacciatore S, et al., 2016, Relative Contribution of Hormonal and Inflammatory Pathways to Uterine Transcriptome Dynamics in Term and Preterm Labor, 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 125A-125A, ISSN: 1933-7191
Cook JR, MacIntyre DA, Sykes L, et al., 2016, Prediction of Cervical Shortening and Preterm Delivery Using Specific Cell Free Plasma MicroRNAs, 63rd Annual Scientific Meeting of the Society for Reproductive Investigation, Publisher: SAGE Publications, Pages: 191A-192A, ISSN: 1933-7205
Cook JR, MacIntyre DA, Kim SH, et al., 2016, Nuclear Factor Kappa-B Functionally Modulates Hsa-miR-146b-3p in Human Myometrial Cells., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 133A-133A, ISSN: 1933-7191
Georgakopoulou N, MacIntyre DA, Cacciatore S, et al., 2016, Early Second Trimester Plasma Metabolome Signatures of Cervical Shortening and Preterm Delivery., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 208A-208A, ISSN: 1933-7191
Brown R, Kindinger L, Lee Y, et al., 2016, Characterisation of the Vaginal Microbiome in Patients Subsequently Experiencing Preterm Prelabour Rupture of Membranes., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 291A-291A, ISSN: 1933-7191
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- Citations: 1
Kindinger L, MacIntyre D, Lee Y, et al., 2016, Identification of Vaginal Microbial Communities Associated with Specific Etiologies of Preterm Birth., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 59A-60A, ISSN: 1933-7191
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- Citations: 1
Brown R, Lee Y, Bains S, et al., 2016, Activator Protein 1 Is a Key Modulator of NOD1 and NOD2 Inflammatory Activation in Vaginal Epithelial Cells, 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 125A-126A, ISSN: 1933-7191
Mitra A, MacIntyre D, Lee Y, et al., 2016, Cervical Intraepithelial Neoplasia Disease Progression Is Associated with Increased Vaginal Microbiome Diversity., 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 66A-66A, ISSN: 1933-7191
Mitra A, Maclntyre D, Lee Y, et al., 2016, Characterisation of the vaginal microbiome in cervical intraepithelial neoplasia, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 75-75, ISSN: 0140-6736
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- Citations: 3
Brown R, Kindinger L, Lee YS, et al., 2016, Role of the vaginal microbiome in preterm prelabour rupture of the membranes: an observational study, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 22-22, ISSN: 0140-6736
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- Citations: 6
Holmes E, Nicholson JK, Darzi AW, et al., 2016, Metabolic Phenotyping in Personalized and Public Healthcare, ISBN: 9780128003442
Metabolic Phenotyping in Personalized and Public Healthcare provides information on the widespread recognition that a personalized or stratified approach to patient treatment may offer a more efficient and effective healthcare solution than phenotype-led approaches. In order to achieve that objective, a deep personal description is required at the level of the genome, proteome, metabolome, or preferably a combination of these aided by technology. This book, edited and written by the outstanding luminaries of this evolving field, evaluates metabolic profiling and its uses across personalized and population healthcare, while also covering the advent of new technology fields, such as surgical metabonomics. In addition, the text presents specific examples of where this technology has been used clinically and with efficacy, pointing towards a framework and protocol for usage as it hits the clinical mainstream.
Holmes E, MacIntyre D, Modi N, et al., 2016, Handing on health to the next generation: Early life exposures, Metabolic Phenotyping in Personalized and Public Healthcare, Pages: 213-264, ISBN: 9780128003442
In this chapter, the role of metabolic phenotyping is described in relation to the improved understanding of the complex biochemical processes that occur in the fetus and in early life. The reasons for the importance of this type of medical supervision are discussed, and the factors that operate both in utero and in the first stages of a baby's life are given. The development of the metabolic phenotype as life begins and continues is explained, including the importance of symbiotic bacteria (the microbiome). The changing metabolic phenotyping in various conditions such as premature birth, maternal obesity, gestational diabetes, pre-eclampsia, and others is discussed in detail. Postnatal factors that influence ongoing health are then discussed in relation to metabolic processes. Finally, a strategy is proposed for monitoring infant and maternal health using metabolic phenotyping.
Jiménez B, MacIntyre D, 2016, NMR metabolic phenotyping in clinical studies, Encyclopedia of Spectroscopy and Spectrometry, Pages: 140-145, ISBN: 9780128032244
Metabolic phenotyping comprises the determination of the metabolic signatures of biofluids and tissues. Differences in such metabolic profiles permit the stratification of individuals according to underlying biochemical status. This information allows objective assessment of health status including disease risk, diagnosis and prognosis, treatment response, drug metabolism, and toxicity. A key analytical platform used for metabolic phenotyping is nuclear magnetic resonance (NMR) spectroscopy due to its robustness, reproducibility, inherent quantitative nature, and capacity to be automated for high throughput. In this article, the main challenges faced in NMR-based metabolic phenotyping studies are explored and the role of phenome centers in the translation of NMR spectroscopy to clinical settings is described.
Mitra A, MacIntyre D, lee YS, et al., 2015, Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity, Scientific Reports, Vol: 5, ISSN: 2045-2322
Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression.
Kim SH, MacIntyre DA, Hanyaloglu AC, et al., 2015, The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alpha i) signalling, Molecular and Cellular Endocrinology, Vol: 420, Pages: 11-23, ISSN: 1872-8057
Sykes L, Rasheed Z, Lee Y, et al., 2015, 15-deoxy-Δ<SUP>12,14</SUP> Prostaglandin J<sub>2</sub> inhibits IL-1<i>β</i>-induced contraction associated protein and pro-inflammatory cytokine expression in human cultured amniocytes and myocytes, Publisher: WILEY-BLACKWELL, Pages: E3-E3, ISSN: 1470-0328
Pirianov G, MacIntyre DA, Lee Y, et al., 2015, Specific inhibition of c-Jun N-terminal kinase delays preterm labour and reduces mortality, Reproduction, Vol: 150, Pages: 269-277, ISSN: 1741-7899
Preterm labour (PTL) is commonly associated with infection and/or inflammation. Lipopolysaccharide (LPS) from different bacteria can be used to independently or mutually activate Jun N-terminal kinase (JNK)/AP1- or NF-κB-driven inflammatory pathways that lead to PTL. Previous studies using Salmonella abortus LPS, which activates both JNK/AP-1 and NF-κB, showed that selective inhibition of NF-κB delays labour and improves pup outcome. Where labour is induced using Escherichia coli LPS (O111), which upregulates JNK/AP-1 but not NF-κB, inhibition of JNK/AP-1 activation also delays labour. In this study, to determine the potential role of JNK as a therapeutic target in PTL, we investigated the specific contribution of JNK signalling to S. Abortus LPS-induced PTL in mice. Intrauterine administration of S. Abortus LPS to pregnant mice resulted in the activation of JNK in the maternal uterus and fetal brain, upregulation of pro-inflammatory proteins COX-2, CXCL1, and CCL2, phosphorylation of cPLA2 in myometrium, and induction of PTL. Specific inhibition of JNK by co-administration of specific D-JNK inhibitory peptide (D-JNKI) delayed LPS-induced preterm delivery and reduced fetal mortality. This is associated with inhibition of myometrial cPLA2 phosphorylation and proinflammatory proteins synthesis. In addition, we report that D-JNKI inhibits the activation of JNK/JNK3 and caspase-3, which are important mediators of neural cell death in the neonatal brain. Our data demonstrate that specific inhibition of TLR4-activated JNK signalling pathways has potential as a therapeutic approach in the management of infection/inflammation-associated PTL and prevention of the associated detrimental effects to the neonatal brain.
Mitra A, MacIntyre DA, Lee YS, et al., 2015, THE VAGINAL MICROBIOME OF WOMEN WITH CERVICAL INTRAEPITHELIAL NEOPLASIA, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 25, Pages: 976-977, ISSN: 1048-891X
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- Citations: 3
Sykes L, Thomson KR, Boyce EJ, et al., 2015, Sulfasalazine augments a pro-inflammatory response in IL-1β-stimulated amniocytes and myocytes., Immunology, Vol: 146, Pages: 630-644, ISSN: 0019-2805
Preterm birth occurs in 10% of pregnancies and is a major cause of neonatal morbidity and mortality. The majority of cases of early preterm labour (PTL) are associated with infection/inflammation, which places the fetal central nervous system at risk. Targeting immune activation is therefore an appealing therapeutic strategy for the prevention of PTL and neonatal brain injury. The expression of many labour-associated and inflammatory-response genes are controlled by the transcription factors NF-κB and Activator Protein-1 (AP-1), which makes them therapeutic targets of interest. Sulfasalazine (SASP) has been shown to inhibit NF-κB and reduce LPS-induced cytokine concentrations in fetal membrane explants and reduce the rate of E.coli-induced PTL in mice. Its effects upon AP-1 in the context of pregnancy are unknown. In this study the effect of SASP on IL-1β-induced NF-κB and AP-1 activity, cytokine production and COX-2 expression was examined in amniocytes and myocytes. A supra-therapeutic concentration (5 mM) was required to inhibit IL-1β-induced NF-κB (p<0.0001) in amniocytes and IL-1β-induced NF-κB (p<0.01), AP-1 (p<0.01) and COX-2 (p<0.05) in myocytes. Despite inhibiting IL-1β-induced cytokines, a basal increase in IL-6 (p<0.01), IL-8 (p<0.0001) and TNF-α (p<0.001) was seen with SASP 5 mM in amniocytes, and significant cytotoxic effects were seen in myocytes. The therapeutic concentration of 0.015 mM had no inhibitory effects on pro-inflammatory mediators, but led to an augmented response to IL-1β-induced IL-6 (p<0.01), IL-8 (p<0.05) and TNF-α (p<0.05) in amniocytes and IL-8 (p<0.05) in myocytes. SASP is therefore an unlikely therapeutic candidate for the prevention of inflammation-induced preterm labour. This article is protected by copyright. All rights reserved.
Kindinger LM, Poon LC, Cacciatore S, et al., 2015, The effect of gestational age and cervical length measurements in the prediction of spontaneous preterm birth in twin pregnancies: an individual patient level meta-analysis, Bjog-An International Journal of Obstetrics and Gynaecology, Vol: 123, Pages: 877-884, ISSN: 1471-0528
ObjectiveTo assess the effect of gestational age (GA) and cervical length (CL) measurements at transvaginal ultrasound (TVUS) in the prediction of preterm birth in twin pregnancy.DesignIndividual patient data (IPD) meta-analysis.SettingInternational multicentre study.PopulationAsymptomatic twin pregnancy.MethodsMEDLINE and EMBASE searches were performed and IPD obtained from authors of relevant studies. Multinomial logistic regression analysis determined probabilities for birth at ≤28+0, 28+1 to 32+0, 32+1 to 36+0, and ≥36+1 weeks as a function of GA at screening and CL measurements.Main outcome measuresPredicted probabilities for preterm birth at ≤28+0, 28+1 to 32+0, and 32+1 to 36+0.ResultsA total of 6188 CL measurements were performed on 4409 twin pregnancies in 12 studies. Both GA at screening and CL had a significant and non-linear effect on GA at birth. The best prediction of birth at ≤28+0 weeks was provided by screening at ≤18+0 weeks (P < 0.001), whereas the best prediction of birth between 28+1 and 36+0 weeks was provided by screening at ≥24+0 weeks (P < 0.001). Negative prediction value of 100% for birth at ≤28+0 weeks is achieved at CL 65 mm and 43 mm at ultrasound GA at ≤18+0 weeks and at 22+1 to 24+0 weeks, respectively.ConclusionIn twin pregnancies, prediction of preterm birth depends on both CL and the GA at screening. When CL is <30 mm, screening at ≤18+0 weeks is most predictive for birth at ≤28+0 weeks. Later screening at >22+0 weeks is most predictive of delivery at 28+1 to 36+0 weeks. In twins, we recommend CL screening in twins to commence from ≤18+0 weeks.
Migale R, Herbert BR, Lee YS, et al., 2015, Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor., American Journal of Pathology, Vol: 185, Pages: 2390-2401, ISSN: 1525-2191
Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at day 16 of gestation. Although control (phosphate-buffered saline)-treated animals were delivered at term approximately 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 were delivered 7 ± 2 hours p.i., O55:B5 were delivered 10 ± 3 hours p.i., O127:B8 were delivered 16 ± 10 hours p.i., and O128:B12 were delivered 17 ± 2 hours p.i. (data are given as means ± SD). A correlation between the onset of preterm birth and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in both myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. This may account for some reported differences in models of infection/inflammation-induced preterm labor. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models.
Kindinger L, MacIntyre D, Teoh TG, et al., 2015, Change in cervical length for the prediction of preterm birth with prepregnancy excisional cervical treatment, Publisher: WILEY-BLACKWELL, Pages: 54-54, ISSN: 1470-0328
Kindinger L, MacIntyre D, Teoh TG, et al., 2015, Excisional cervical treatment and subsequent cervical volume in pregnancy, Publisher: WILEY-BLACKWELL, Pages: 56-57, ISSN: 1470-0328
Kindinger L, MacIntyre D, Teoh TG, et al., 2015, The cerclage and cervical vascularity: a prospective longitudinal study in pregnancy, Publisher: WILEY-BLACKWELL, Pages: 79-79, ISSN: 1470-0328
Cook JR, Macintyre DA, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, Publisher: WILEY-BLACKWELL, Pages: 226-226, ISSN: 1470-0328
MacIntyre DA, Chandiramani M, Lee YS, et al., 2015, The vaginal microbiome during pregnancy and the postpartum period in a European population, Scientific Reports, Vol: 5, Pages: 1-9, ISSN: 2045-2322
The composition and structure of the pregnancy vaginal microbiome may influence susceptibility to adverse pregnancy outcomes. Studies on the pregnant vaginal microbiome have largely been limited to Northern American populations. Using MiSeq sequencing of 16S rRNA gene amplicons, we characterised the vaginal microbiota of a mixed British cohort of women (n = 42) who experienced uncomplicated term delivery and who were sampled longitudinally throughout pregnancy (8–12, 20–22, 28–30 and 34–36 weeks gestation) and 6 weeks postpartum. We show that vaginal microbiome composition dramatically changes postpartum to become less Lactobacillus spp. dominant with increased alpha-diversity irrespective of the community structure during pregnancy and independent of ethnicity. While the pregnancy vaginal microbiome was characteristically dominated by Lactobacillus spp. and low alpha-diversity, unlike Northern American populations, a significant number of pregnant women this British population had a L. jensenii-dominated microbiome characterised by low alpha-diversity. L. jensenii was predominantly observed in women of Asian and Caucasian ethnicity whereas L. gasseri was absent in samples from Black women. This study reveals new insights into biogeographical and ethnic effects upon the pregnancy and postpartum vaginal microbiome and has important implications for future studies exploring relationships between the vaginal microbiome, host health and pregnancy outcomes.
Cook JR, MacIntyre DA, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, American Journal of Obstetrics and Gynecology, Vol: 213, Pages: 65.e1-65.e9, ISSN: 0002-9378
Objective: MicroRNAs (miRNAs) play a modulatory role in pathways that lead to labor onset, although oxytocin is known to modulate gene expression within the myometrium. We aimed to identify miRNAs whose expression is regulated by oxytocin in pregnant human myometrium. Study Design: Myometrial miRNA expression profiles were compared between samples collected from women at term before the onset of labor (no labor; n= 8) and after labor onset after early exogenous oxytocin treatment (n= 8). Multivariate modelling was used to assess differences in miRNA profiles. Biologic validation was undertaken on 3 independent patient cohorts (no labor, n= 10; labor induced with oxytocin, n= 8; and spontaneous labor with no oxytocin treatment, n= 10). Invitro studies that used primary myocytes were undertaken to assess target miRNA expression after oxytocin treatment. Target genes of candidate miRNAs were identified in silico and cross-referenced with genes that are known to be associated with labor or expressed in myometrium. Results: In total, 1309 miRNAs were analyzed by microarray, of which 494 were detected in human myometrium. Multivariate modeling identified 12 target miRNAs the differential expression of which was most responsible for the observed separation of the 2 patient populations in the primary discovery cohorts. Biologic validation in the independent secondary sample cohorts showed that oxytocin independently regulated 5 miRNAs (hsa-miR-146b-3p, hsa-miR-196b-3p, hsa-miR-223-3p, hsa-miR-873-5p, and hsa-miR-876-5p). Additionally, hsa-miR-146b-3p was increased both in labor that was induced with oxytocin and in myometrium from spontaneous labor with no oxytocin treatment compared with no labor samples. Four of the validated miRNAs (hsa-miR-146a-5p, hsa-miR-146b-3p, hsa-miR-196b-3p, and hsa-miR-876-5p) were expressed in primary human myocytes; oxytocin treatment of these cells replicated the directional changes that were observed invivo. Conclusion: Oxytocin alters the e
Cook J, MacIntyre D, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, Publisher: Elsevier, Pages: E1-E9, ISSN: 1097-6868
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