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1.  Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner 
Human Reproduction (Oxford, England)  2014;29(6):1161-1172.
Does triiodothyronine (T3) regulate the secretion of angiogenic growth factors and cytokines by human decidual cells isolated from early pregnancy?
T3 modulates the secretion of specific angiogenic growth factors and cytokines, with different regulatory patterns observed amongst various isolated subpopulations of human decidual cells and with a distinct change between the first and second trimesters of pregnancy.
Maternal thyroid dysfunction during early pregnancy is associated with complications of malplacentation including miscarriage and pre-eclampsia. T3 regulates the proliferation and apoptosis of fetal-derived trophoblasts, as well as promotes the invasive capability of extravillous trophoblasts (EVT). We hypothesize that T3 may also have a direct impact on human maternal-derived decidual cells, which are known to exert paracrine regulation upon trophoblast behaviour and vascular development at the uteroplacental interface.
This laboratory-based study used human decidua from first (8–11 weeks; n = 18) and second (12–16 weeks; n = 12) trimester surgical terminations of apparently uncomplicated pregnancies.
Primary cultures of total decidual cells, and immunomagnetic bead-isolated populations of stromal-enriched (CD10+) and stromal-depleted (CD10−) cells, uterine natural killer cells (uNK cells; CD56+) and macrophages (CD14+) were assessed for thyroid hormone receptors and transporters by immunocytochemistry. Each cell population was treated with T3 (0, 1, 10, 100 nM) and assessments were made of cell viability (MTT assay) and angiogenic growth factor and cytokine secretion (immunomediated assay). The effect of decidual cell-conditioned media on EVT invasion through Matrigel® was evaluated.
Immunocytochemistry showed the expression of thyroid hormone transporters (MCT8, MCT10) and receptors (TRα1, TRβ1) required for thyroid hormone-responsiveness in uNK cells and macrophages from the first trimester. The viability of total decidual cells and the different cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P < 0.05) and increased angiopoietin-2 secretion by stromal-depleted cells (P < 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P < 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P < 0.05), and reduced granulocyte macrophage colony stimulating factor (P < 0.01), IL-8 (P < 0.05), IL-10 (P < 0.01), IL-1β (P < 0.05) and monocyte chemotactic protein -1 (P < 0.001) secretion by macrophages, but increased tumour necrosis factor-α secretion by stromal-depleted cells (P < 0.05) and increased IL-6 by uNK cells (P < 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P < 0.01) but did not affect cytokine secretion by uNK cells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro.
Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo.
Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory ‘switch’ in T3 responsiveness between the first and second trimesters, and support the notion that the timely and early correction of maternal thyroid dysfunction is critical in influencing pregnancy outcomes.
This study is funded by Wellbeing of Women (RG/1082/09 to S.Y.C., M.D.K., J.A.F., L.S.L., G.E.L.) and Action Medical Research – Henry Smith Charity (SP4335 to M.D.K., S.Y.C., L.S.L., J.A.F.). The authors have no conflicts of interest to disclose.
PMCID: PMC4017942  PMID: 24626803
decidua; triiodothyronine; cytokines; angiogenic growth factors; extravillous trophoblast
2.  Manipulation of PBF/PTTG1IP Phosphorylation Status; a Potential New Therapeutic Strategy for Improving Radioiodine Uptake in Thyroid and Other Tumors 
The clinical effectiveness of ablative radioiodine treatment of thyroid tumors is limited by the availability of the sodium iodide symporter (NIS) at the plasma membrane (PM) for uptake of 131I. A significant proportion of well-differentiated thyroid tumors are unable to concentrate sufficient radioiodine for effective therapy, and in other tumor models such as breast tumors, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient.
Pituitary tumor–transforming gene-binding factor (PBF; PTTG1IP) is overexpressed in multiple cancers and significantly decreases NIS expression at the PM. The goal of this study was to identify a method by which PBF repression of NIS may be overcome in human tumors.
Here, we identify PBF as a tyrosine phosphoprotein that specifically binds the proto-oncogene tyrosine protein kinase Src in mass spectrometry, glutathione S-transferase pulldown and coimmunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance to the treatment of thyroid cancer, PP1 stimulates iodide uptake by transfected NIS in TPC1 thyroid carcinoma cells and entirely overcomes PBF repression of iodide uptake in human primary thyroid cells.
We propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumors.
PMCID: PMC4207948  PMID: 23678037
3.  A Simulation Study of the Self-Assembly of Coarse-Grained Skin Lipids 
Soft matter  2012;8(17):4802-4814.
Computer simulations are an attractive means by which to probe the self-assembly and molecular level organization of lipids in biological membranes. In this work, we study a simple skin lipid system to demonstrate the ability of the coarse-grained models used for fatty acids, cholesterol, and water to self-assemble, thus validating the models for use in further studies of the complex lipid mixtures found in the outermost layer of the skin. Specifically, the ability of the models to predict the correct self-assembled structures from molecular dynamics simulations is compared against those seen experimentally and from all-atom simulations of preassembled bilayers. The nature of the molecular interactions and their roles in the self-assembly process is elucidated and heuristics for self-assembly established. Additionally, the coarse-grained models have been used to characterize the effect of varying cholesterol composition on bilayer properties and the mechanism of bilayer destabilization by short and long chain fatty acids in the presence of cholesterol.
PMCID: PMC3418889  PMID: 22899964
Self-assembly; fatty acids; cholesterol; water; bilayer; molecular dynamics
4.  Differential Triiodothyronine Responsiveness and Transport by Human Cytotrophoblasts from Normal and Growth-Restricted Pregnancies 
Context: Abnormal placentation in human pregnancy is associated with intrauterine fetal growth restriction (IUGR). Our group has previously reported the association between severe IUGR, lower fetal circulating concentrations of thyroid hormones (THs), and altered expression of TH receptors and TH transporters within human placental villi. We postulate that altered TH bioavailability to trophoblasts may contribute to the pathogenesis of IUGR.
Design and Objective: Cytotrophoblasts were isolated from normal and IUGR human placentae to compare their responsiveness to T3 and their capability for T3 transport.
Results: Compared with normal cytotrophoblasts, the viability of IUGR cytotrophoblasts (assessed by methyltetrazoleum assay) was significantly reduced (P < 0.001), whereas apoptosis (assessed using caspase 3/7 activity and M30 immunoreactivity) was significantly increased after T3 treatment for 48 h (P < 0.001 and P < 0.01, respectively). The secretion of human chorionic gonadotropin was significantly increased by IUGR cytotrophoblasts compared with normal cytotrophoblasts (P < 0.001), independently of T3 treatment. Net transport of [125I]T3 was 20% higher by IUGR cytotrophoblasts compared with normal cytotrophoblasts (P < 0.001), and this was accompanied by a 2-fold increase in the protein expression of the TH transporter, monocarboxylate transporter 8, as assessed by Western immunoblotting (P < 0.01).
Conclusions: IUGR cytotrophoblasts demonstrate altered responsiveness to T3 with significant effects on cell survival and apoptosis compared with normal cytotrophoblasts. Increased monocarboxylate transporter 8 expression and intracellular T3 accumulation may contribute to the altered T3 responsiveness of IUGR cytotrophoblasts.
Cytotrophoblasts from growth-restricted pregnancies demonstrate increased net T3 uptake and increased T3 responsiveness, which affects cell survival and apoptosis compared with cytotrophoblasts from normal pregnancies.
PMCID: PMC3050105  PMID: 20660035
5.  Monocarboxylate transporter 8 expression in the human placenta : the effects of severe intrauterine growth restriction 
The Journal of endocrinology  2006;189(3):465-471.
Thyroid hormones (THs) are essential for normal fetal development, with even mild perturbation in maternal thyroid status in early pregnancy being associated with neurodevelopmental delay in children. Transplacental transfer of maternal THs is critical, with increasing evidence suggesting a role for T3 in development and function of the placenta itself, as well as in development of the central nervous and other organ systems. Intrauterine growth restriction (IUGR) is associated with fetal hypothyroxinaemia, a factor that may contribute to neurodevelopmental delay. The recent description of monocarboxylate transporter 8 (MCT8) as a powerful and specific TH membrane transporter, and the association of MCT8 mutations with profound neurodevelopmental delay, led us to explore MCT8 expression in placenta. We describe the expression of MCT8 in normal human placenta throughout gestation, and in normal third trimester placenta compared with that associated with IUGR using quantitative RT-PCR. MCT8 mRNA was detected in placenta from early first trimester, with a significant increase with advancing gestation (p=0.007). In the early third trimester, MCT8 mRNA was increased in IUGR placenta compared with normal samples matched for gestational age (p<0.05) but there was no difference between IUGR and normal placenta in the late third trimester. Western immunoblotting findings in IUGR and normal placentae were in accord with mRNA data. MCT8 immunostaining was demonstrated in villous cytotrophoblast and syncytiotrophoblast as well as extravillous trophoblast cells from the first trimester onwards with increasingly widespread immunoreactivity seen with advancing gestation.
Expression of MCT8 in placenta from early gestation is compatible with an important role in TH transport during fetal development and a specific role in placental development. Altered expression in placenta associated with IUGR may reflect a compensatory mechanism attempting to increase T3 uptake by trophoblast cells.
PMCID: PMC2869027  PMID: 16731778
thyroid hormone; MCT8; placenta; intrauterine growth restriction
6.  Cost analysis for cancer subgroups 
British Journal of Cancer  2009;100(9):1513.
PMCID: PMC2694430  PMID: 19401705
7.  The potential impact on costs and staffing of introducing clinical networks and British Association of Perinatal Medicine standards to the delivery of neonatal care 
Objective: To produce models to estimate the impact of introducing clinical networks and the 2001 BAPM standards to the delivery of neonatal care.
Design: Prospective observational study using a geographically defined population and data collected by questionnaire on staffing levels and cot availability.
Setting: Trent Health Region UK.
Subjects: All infants born to Trent resident mothers at or before 32 weeks gestation between 1 January 1998 and 31 December 1999. Staffing numbers and cot availability for neonatal care in 2001.
Methods: A modelling exercise was carried out using information for all neonatal admissions for Trent resident infants. Three models were investigated: (a) the current care provision; (b) a network where three lead centres provided the intensive care for the region and the remaining units provided either high dependency or special care alone; (c) a network where six lead centres provided the intensive care for the region and the remaining units provided either high dependency or special care alone. Overall costings, staffing levels, and cot requirements were calculated for each model. Data on staffing levels and cot availability were used to calculate current care provision costings.
Results: The current cost of running the service is approximately £33.35 million, although a proportion of nursing posts are currently unfilled. Estimates for the introduction of a three centre model meeting BAPM 2001 standards range from £37.31 to £43.40 million. Equivalent figures for the six centre model were: £36.32 to £42.62 million. Approximately 370 and 230 babies a year would be involved in transfer in the three and six centre models respectively. This is in contrast with 374 and 368 urgent transfers that actually took place in 1998 and 1999 respectively.
Conclusion: The costs associated with the introduction of managed clinical networks and meeting BAPM standards of care are not excessive, especially when considered against the likely implementation timetable of perhaps 7–10 years. Attracting and retaining sufficient staff will pose the major challenge.
PMCID: PMC1721690  PMID: 15102727
8.  Being economical with the truth: how to make your idea appear cost effective 
Emergency Medicine Journal : EMJ  2002;19(4):301-304.
The importance of presentation and evaluation of economic data with regard to the cost effectiveness of a health care intervention are discussed.
PMCID: PMC1725899  PMID: 12101135
9.  An introduction to economic evaluation 
Emergency Medicine Journal : EMJ  2002;19(3):198-201.
PMCID: PMC1725884  PMID: 11971826
10.  Cost effectiveness of statins 
Heart  2000;83(6):713.
PMCID: PMC1760882  PMID: 10885942
11.  Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment 
Heart  1999;82(3):325-332.
OBJECTIVES—To estimate the cost effectiveness of statin treatment in preventing coronary heart disease (CHD) and to examine the effect of the CHD risk level targeted and the cost of statins on the cost effectiveness of treatment.
DESIGN—Cohort life table method using data from outcome trials.
MAIN OUTCOME MEASURES—The cost per life year gained for lifelong statin treatment at annual CHD event risks of 4.5% (secondary prevention) and 3.0%, 2.0%, and 1.5% (all primary prevention), with the cost of statins varied from £100 to £800 per year.
RESULTS—The costs per life year gained according to annual CHD event risk were: for 4.5%, £5100; 3.0%, £8200; 2.0%, £10 700; and 1.5%, £12 500. Reducing the cost of statins increases cost effectiveness, and narrows the difference in cost effectiveness across the range of CHD event risks.
CONCLUSIONS—At current prices statin treatment for secondary prevention, and for primary prevention at a CHD event risk 3.0% per year, is as cost effective as many treatments in wide use. Primary prevention at lower CHD event risks (< 3.0% per year) is less cost effective and unlikely to be affordable at current prices and levels of health service funding. As the cost of statins falls, primary prevention at lower risk levels becomes more cost effective. However, the large volume of treatment needed will remain a major problem.

Keywords: coronary artery disease; cost effectiveness; statins; primary prevention; secondary prevention
PMCID: PMC1729169  PMID: 10455083
13.  Economic burden of environmental tobacco smoke on Hong Kong families: scale and impact 
STUDY OBJECTIVE: To examine the financial cost of doctor consultations for cough, phlegm, and wheeze in children living in a home where family members smoke compared with those not exposed to environmental tobacco smoke. To model these costs to provide the Territory of Hong Kong with estimates of potentially avoidable health care resource use. DESIGN: Cross sectional questionnaire survey. SUBJECTS AND SETTING: All children (10,615) in classes primary 3 to 6 (aged 8-13 years) attending 27 schools in two districts of Hong Kong in 1992 and their parents. MEASUREMENTS AND MAIN RESULTS: Doctor consultations during the previous three months for symptoms of either cough, phlegm or wheeze were higher in younger children, ranging from 22.9% in 8 year olds to 8.4% in those aged 12 or over. For those children living in homes with one, or more than one, smoker category (there were four categories of smokers: father, mother, siblings, others), the adjusted odds ratios (95% confidence intervals) for a doctor consultation for any of these symptoms were 1.15 (1.01, 1.31) and 1.38 (1.14, 1.67) respectively. Using US$15 as the minimum cost incurred per consultation, the expected direct cost per annum per child of doctor consultations was 14% higher for children living in a one smoker category home and 25% for two or more compared with exposure to no smokers in the home. Using these values on a territory wide basis, the annual avoidable direct cost associated with exposure to tobacco smoke in children from birth to 12 years of age ranged from US$338,042 to US$991,591. CONCLUSIONS: Exposure to environmental tobacco smoke not only provides a respiratory health risk for children but also an avoidable excess cost to the family's financial resources and health service providers.
PMCID: PMC1756610  PMID: 9604042
14.  Cost of care for a geographically determined population of low birthweight infants to age 8-9 years. II. Children with disability. 
AIM: To determine the cost of health and educational service provision for low birthweight children with a clinical disability. METHODS: Cohort study of a geographically defined population in five health districts that comprise the County of Merseyside was undertaken. All children with a clinical disability born in 1980 and 1981 to mothers resident in the County of Merseyside were followed up to age 8-9 years. The cost of care associated with the initial admission to the neonatal special/intensive care unit and subsequent use of hospital, family practitioner, and special education services was assessed. RESULTS: There were 52 children with a disability; the disability rate in children of birthweight < or = 2000 g was estimated at 7.7%. Of the total expenditure to age 8-9 years, special education was the largest category (52%) and neonatal care accounted for 35%. The disabled children accounted for 38% of the cost of the whole cohort of 693 disabled and non-disabled children who weighed < or = 2000 g at birth. CONCLUSION: In a cohort of low birthweight children, those who are disabled account for a disproportionate amount of the total expenditure to age 8-9. The cost of long term care for disabled young persons and adults will increasingly dominate the cost of care for the whole cohort of low birthweight children.
PMCID: PMC2528526  PMID: 8777658
15.  Cost of care for a geographically determined population of low birthweight infants to age 8-9 years. I. Children without disability. 
AIM: To determine the extra cost of healthcare associated with low birthweight, in a cohort study of a geographically defined population in five health districts that comprise Merseyside. METHODS: The study comprised all children of birthweight < or = 1500 g and a 10% random sample of those weighing 1501-2000 g, without clinical disability, born in 1980 and 1981 to mothers resident in Merseyside, and their controls, matched by age, sex, and school class, followed up to age 8-9 years. RESULTS: The cost of care associated with the initial admission to the neonatal special/intensive care unit and subsequent use of hospital and family practitioner services was assessed. There were 641 survivors without disability and 227 non-survivors who weighed < or = 2000 g at birth. The mean cost of neonatal care per low birthweight child was 13 times greater than for a control child. For children weighing < or = 1000 g at birth, neonatal costs were 55 times greater than for the control children. Low birthweight children continue to use hospital and family practitioner services more intensively than controls to age 8-9 years. CONCLUSION: Low birthweight children used hospital and family practitioner services more intensively throughout the follow up period. Whether the increased use of health services persists into adolescence and adulthood is yet to be determined.
PMCID: PMC2528521  PMID: 8777657
16.  The Dental Practitioner's Role in Emergency Health Services 
In a national disaster, the medical profession would lose physicians and auxiliary personnel and would need assistance. Canada's 22,000 physicians and 85,000 nurses are located for the most part in potential target areas. Survivors among Canada's 6396 dentists could supply 30% reinforcement. The dentist's training, his manual dexterity and experience acquired in the management of hemorrhage, shock, débridement, suturing, reduction and immobilization of fractures, and control of pain and infection would be valuable. Additional functions he could perform would be first-aid, including but not limited to artificial respiration, early management of chest wounds, preparation of casualties for movement, and assistance in general surgical procedures. Dentists with special training in anesthesia, oral surgery or public health could be of particular value in relieving anesthetists, surgeons, radiologists and public health officers of some of their duties. Joint training of physicians and dentists in mass casualty care could increase the efficiency of the team work in disaster and is being considered by many medical and dental faculties.
PMCID: PMC1936900  PMID: 6015739

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