Dharmadhikari A.V.,Baylor College of Medicine |
Kalinichenko V.V.,Perinatal Institute |
Stankiewicz P.,Baylor College of Medicine
Current Genomics | Year: 2015
The FOXF1 (Forkhead box F1) gene, located on chromosome 16q24.1 encodes a member of the FOX family of transcription factors characterized by a distinct forkhead DNA binding domain. FOXF1 plays an important role in epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog pathway. Heterozygous point mutations and genomic deletions involving FOXF1 have been reported in newborns with a lethal lung developmental disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV). In addition, genomic deletions upstream to FOXF1 identified in ACDMPV patients have revealed that FOXF1 expression is tightly regulated by distal tissue-specific enhancers. Interestingly, FOXF1 has been found to be incompletely paternally imprinted in human lungs; characterized genomic deletions arose de novo exclusively on maternal chromosome 16, with most of them being Alu-Alu mediated. Regulation of FOXF1 expression likely utilizes a combination of chromosomal looping, differential methylation of an upstream CpG island overlapping GLI transcription factor binding sites, and the function of lung-specific long non-coding RNAs (lncRNAs). Foxf1 knock-out mouse models demonstrated its critical role in mesoderm differentiation and in the development of pulmonary vasculature. Additionally, epigenetic inactivation of FOXF1 has been reported in breast and colorectal cancers, whereas overexpression of FOXF1 has been associated with a number of other human cancers, e.g. medulloblastoma and rhabdomyosarcoma. Constitutional duplications of FOXF1 have recently been reported in congenital intestinal malformations. Thus, understanding the genomic and epigenetic complexity at the FOXF1 locus will improve diagnosis, prognosis, and treatment of ACDMPV and other human disorders associated with FOXF1 alterations. © 2015, Current Genomics, All rights Reserved.
Gardosi J.,Perinatal Institute |
Gardosi J.,University of Warwick |
Giddings S.,Perinatal Institute |
Clifford S.,Perinatal Institute |
And 2 more authors.
BMJ Open | Year: 2013
Objective: To assess the effect that accreditation training in fetal growth surveillance and evidence-based protocols had on stillbirth rates in England and Wales. Design: Analysis of mortality data from Office of National Statistics. Setting: England and Wales, including three National Health Service (NHS) regions (West Midlands, North East and Yorkshire and the Humber) which between 2008 and 2011 implemented training programmes in customised fetal growth assessment. Population: Live births and stillbirths in England and Wales between 2007 and 2012. Main outcome measure: Stillbirth. Results: There was a significant downward trend (p=0.03) in stillbirth rates between 2007 and 2012 in England to 4.81/1000, the lowest rate recorded since adoption of the current stillbirth definition in 1992. This drop was due to downward trends in each of the three English regions with high uptake of accreditation training, and led in turn to the lowest stillbirth rates on record in each of these regions. In contrast, there was no significant change in stillbirth rates in the remaining English regions and Wales, where uptake of training had been low. The three regions responsible for the record drop in national stillbirth rates made up less than a quarter (24.7%) of all births in England. The fall in stillbirth rate was most pronounced in the West Midlands, which had the most intensive training programme, from the preceding average baseline of 5.73/1000 in 2000-2007 to 4.47/1000 in 2012, a 22% drop which is equivalent to 92 fewer deaths a year. Extrapolated to the whole of the UK, this would amount to over 1000 fewer stillbirths each year. Conclusions: A training and accreditation programme in customised fetal growth assessment with evidencebased protocols was associated with a reduction in stillbirths in high-uptake areas and resulted in a national drop in stillbirth rates to their lowest level in 20 years.
News Article | December 8, 2016
CINCINNATI - Researchers cracked the complete genetic code of individual cells in healthy and diseased human lung tissues to find potential new molecular targets for diagnosing and treating the lethal lung disease Idiopathic Pulmonary Fibrosis (IPF). A team of scientists from Cincinnati Children's Hospital Medical Center, in collaboration with investigators at Cedars-Sinai Medical Center in Los Angeles, publish their findings Dec. 8 in the Journal of Clinical Investigation Insights (JCI Insights). "This paper identifies a number of novel targets and molecular pathways for IPF, for which there are pharmaceutical approaches," said Jeffrey Whitsett MD, lead investigator and co-director of the Perinatal Institute at Cincinnati Children's. "Airway cells can be obtained by brushing the airway or biopsy, and marker genes can be tested to make a diagnosis or monitor treatment." IPF is a common and lethal interstitial lung disease in adults, which means it inflames, scars and reconfigures lung tissues. This causes loss of the air sacs, called alveoli, where oxygen and carbon dioxide are normally exchanged. Similar losses of lung function can occur earlier in life, especially in children with diseases caused by mutations in genes critical for surfactant and maintenance of the lung saccules. Biological processes controlling the formation and function of the lung's alveolar region require precisely orchestrated interactions between diverse epithelial, stromal and immune cells, according to study authors. Despite many years of extensive laboratory studies of whole tissue samples - trying to identify genetic, cellular and molecular processes that fuel lung ailments like IPF - the precise biology has remained elusive. To overcome this, Whitsett and colleagues - including first author and bioinformatician Yan Xu, PhD of Cincinnati Children's - conducted what they believe to be the first-ever single-cell RNA sequence analysis of normal and diseased human lung tissues (all donated with prior informed consent). This provided the authors with a detailed genetic blueprint of all the different epithelial cell types involved in IPF progression and a window to identify aberrant biological processes driving inflammation and fibrosis. Analysis of normal lung epithelial cells found gene patterns linked to fully formed alveolar type 2 lung cells (AT2 cells), which are important for the production of surfactant, a substance containing a complex of proteins critical to breathing. Analysis of diseased IPF cells found genetic markers for lung cells that were in indeterminate states of formation, the authors report. IPF cells had lost the normal genetic control systems needed to guide their functions. This study identifies abnormalities in gene expression that can be targeted for therapy of chronic lung diseases like IPF. Funding support for the research came from the National Institutes of Health (HL122642, HL110967 and HL108793) and the California Institute for Regenerative Medicine (CIRM LA1-06915).
Hodgetts V.A.,Sandwell and West Birmingham Hospitals NHS Trust |
Morris R.K.,University of Birmingham |
Morris R.K.,Academic Unit |
Francis A.,Perinatal Institute |
And 2 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2015
Objectives To assess the effect of timing of folic acid (FA) supplementation during pregnancy on the risk of the neonate being small for gestational age (SGA). Design A population database study and a systematic review with meta-analysis including the results of this population study. Setting and data sources A UK regional database was used for the population study and an electronic literature search (from inception until August 2013) for the systematic review. Participants and included studies Singleton live births with no known congenital anomalies; 111 736 in population study and 188 796 in systematic review. Outcome measures, data extraction and analysis The main outcome was SGA based on customised birthweight centile. Associations are presented as odds ratios (OR) and adjusted odds ratios (aOR), adjusted for maternal and pregnancy-related characteristics. Results Of 108 525 pregnancies with information about FA supplementation, 92 133 (84.9%) had taken FA during pregnancy. Time of commencement of supplementation was recorded in 39 416 pregnancies, of which FA was commenced before conception in 10 036, (25.5%) cases. Preconception commencement of FA supplementation was associated with reduced risk of SGA <10th centile (aOR 0.80, 95% CI 0.71-0.90, P < 0.01) and SGA <5th centile (aOR 0.78, 95% CI 0.66-0.91, P < 0.01). This result was reproduced when the data were pooled with other studies in the systematic review, showing a significant reduction in SGA (<5th centile) births with preconception commencement of FA (aOR 0.75, 95% CI 0.61-0.92, P < 0.006). In contrast, postconception folate had no significant effect on SGA rates. Conclusion Supplementation with FA significantly reduces the risk of SGA at birth but only if commenced preconceptually independent of other risk factors. Systematic review registration This systematic review was prospectively registered with PROSPERO number CRD42013004895. © 2014 Royal College of Obstetricians and Gynaecologists.
PubMed | Cincinnati Childrens Hospital Medical Center, National Autonomous University of Mexico, Perinatal Institute and Baylor College of Medicine
Type: Journal Article | Journal: Journal of the Pediatric Infectious Diseases Society | Year: 2016
Qualitative polymerase chain reaction (PCR) was used to determine the prevalence of fecal excretion of BK virus, JC virus, and simian virus 40 in 1-year-old infants. Overall, 17.8% of 321 specimens from 64.1% of 39 infants were polyomavirus positive. These data suggest that the gastrointestinal tract may be a site of polyomavirus persistence in humans.
Cross-Sudworth F.,Perinatal Institute |
Williams A.,Perinatal Institute |
Herron-Marx S.,Coventry University
Midwifery | Year: 2011
Objective: to explore first- and second-generation Pakistani women's experiences of maternity services and the inter generational differences/comparisons. Design: a retrospective Q methodology study of Pakistani women following childbirth. Setting: two Children's Centres in an inner city in the West Midlands. Participants: women self-identified following distribution of information leaflets at Children's Centres. Fifteen women took part in interviews (Stage one) using a semi-structured design and 16 women participated in the completion of the Q grid sorting (Stage four). Methods: a standard five-stage Q methodology process took place: (1) initial data were gathered using a combination of individual face-to-face and focus group semi-structured community-based interviews (developing the concourse); (2) transcribed interviews were analysed for 'themes'; (3) the themes were reduced to 'statements' that reflected the overall content of the concourse using an unstructured evolving approach (giving the Q set); (4) participants were asked to sort the statements (Q sorting) according to a pre-designed distribution grid providing individual participant response grids; and (5) the response grids were factor analysed using PQ Method (V2.11), which generates clusters of participants rather than clusters of variables. Factor loadings were calculated using factor analysis by principal components with varimax rotation. This produced a list of factors, each of which represents a 'story' of women's experiences of maternity services. Throughout the process, an Urdu interpreter was involved. Findings: six factors were identified: (1) confidence and empowerment of women who had attended higher education and had family support; (2) isolation of some women from both family and maternity services; (3) women who had poor experiences of maternity services but good family support, and wanted opportunities to be involved in service development; (4) women with positive experiences of maternity care and influenced by traditional cultural practices; (5) importance of information and support from health-care professionals; and (6) importance of midwifery care to women. Conclusion: there were no clear inter generational differences identified, but a breadth of opinion and experience that seemed to be influenced by level of both education and social support was found. Whereas some women had few demands of maternity services, those who had less support and those with language barriers had additional needs. Implications for practice: care given should be based on individual need but given within a wider collaborative context in order to support women effectively. Increased maternity service user involvement would also be welcomed for future planning of maternity services. © 2010 Elsevier Ltd.
Tranguch S.,New York University |
Dey S.K.,Perinatal Institute
International Journal of Developmental Biology | Year: 2014
This interview chronicles the story of Sudhansu K. Dey in his journey from Calcutta, India to Kansas City, Kansas, establishing a research enterprise in the field of female reproduction. His research of over four decades has focused specifically on implantation biology using various model systems and reveling the impact of implantation on female reproductive medicine. This interview also reveals qualities of SK's character - his resolution, mentoring spirit, and humble nature - that contributed to his successes. SK is not shy to approach individuals for expertise or help, and in the same spirit, he is ready to offer his help to others irrespective of their positions or stature. He constantly attributes his success to the hard work of his laboratory members, the intellectual stimulation from his collaborators, and the support from his family. His ability to overcome challenges throughout his career is a reminder to students and junior investigators in the scientific community that each individual is endowed with talents and can accomplish their dreams if they pursue them. This interview tells the story of how he progressed from an inquisitive child to becoming a true servant to the cause of science and humankind. © 2014 UBC Press.
Sun X.,Perinatal Institute |
Dey S.K.,Perinatal Institute
Life Sciences | Year: 2014
Increases in emergency room visits due to abuse of designer drugs, popularly known by the street names "K2" and "Spice," are a cause for social, judicial, and clinical concerns. The psychoactive components in these herbal drugs mainly consist of different synthetic cannabinoids, and users of these street drugs are primarily within the age group of 12 to 20 years old. The abusive use of synthetic cannabinoids results in anxiety, nausea, vomiting, tachycardia, elevated blood pressure, tremors, seizures, hallucinations, and paranoid behavior, but the effects of maternal use of synthetic cannabinoids during pregnancy are ambiguous due to limited studies in humans and a relative short history of the drugs. In this review, we discuss the known and potential adverse effects of synthetic cannabinoids on human pregnancy using knowledge gathered from studies in mice and limited studies in humans. In mice, multiple sites and stages of pregnancy are potential targets of synthetic cannabinoids, including preimplantation embryo development, oviductal embryo transport, implantation, placentation, and parturition. It is anticipated that maternal use of synthetic cannabinoids would result in severely compromised female fertility and pregnancy outcome. © 2013 Elsevier Inc. All rights reserved.
Gardosi J.,Perinatal Institute |
Giddings S.,Perinatal Institute |
Buller S.,Perinatal Institute |
Southam M.,Perinatal Institute |
Williams M.,Perinatal Institute
Public Health | Year: 2014
Most stillbirths used to be categorized as 'unexplained' and were considered, by implication, unavoidable. Recent evidence indicates that they represent a combined challenge for public health and for clinical services. Independent case reviews have found that many deaths are associated with a failure to recognize risk factors and to afford them the appropriate standard of care. The majority of normally formed fetal deaths had preceding, unrecognized intrauterine growth failure. Improved training and adoption of standardized protocols has led to increased antenatal detection of fetal growth restriction, and this in turn has resulted in significant reductions in stillbirths in areas with high uptake of the training programme. A comprehensive, evidence-based growth assessment protocol (GAP) is currently being rolled out across the NHS to implement this strategy for stillbirth prevention. © 2014 The Royal Society for Public Health.
Gardosi J.,Perinatal Institute
Journal of Obstetrics and Gynaecology Canada | Year: 2014
Customized growth charts reduce complexity in antenatal care for the expectant mother and her clinicians by improving the distinction between physiological and pathological variation in fetal size. Their application in large databases has improved our understanding of the importance of intrauterine growth restriction and its antenatal recognition. Their implementation into clinical practice, together with the appropriate training and referral protocols, has been shown to reduce the risk of stillbirth. © 2014 Society of Obstetricians and Gynaecologists of Canada.