Roles of surfactant proteins, SP-A and SP-D, in pregnancy and parturition

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Surfactant proteins SP-A and SP-D are important key molecules responsible for pulmonary homeostasis and innate immunity against infectious pathogens. SP-A and SP-D are also found in various parts of the placenta as well as amniotic fluid. The levels of these proteins in the amniotic fluid are good biomarkers of fetal lung maturation. The development of the lungs in fetal growth is important for fetal survival in extrauterine life. In pregnant mice models, a huge increase in SP-A and SP-D levels in the amniotic sac has been reported close to parturition suggesting an important role of these proteins in the hormonal pathway to labour. In this thesis, full length natural and recombinant proteins of human SP-A and SP-D were generated and examined on the maternal-fetal tissues of the placenta (explants of amnion, chorion and decidua) under inflammatory conditions. A range of innate and adaptive immune markers and prostaglandin targets were examined to show that SP-A and SP-D modulate the prostaglandin pathway. Thus, an imbalance in this could potentially lead to disorders such as intrauterine growth retardation and preeclampsia. The cellular basis of immune regulation and prostaglandin pathway was also examined via fractionation of decidual macrophages. Curiously, SP-A and SP-D appears to suppress pro-inflammatory response of decidual macrophages after challenging with LPS. This thesis thus divulges specific and mutually inclusive functions of SP-A and SP-D in the maintenance of pregnancy, protection against intrauterine infection, dampening of inflammation, and premature activation of parturition

Am J Hum Genet

Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development

Surfactant proteins SP-A and SP-D modulate uterine contractile events in ULTR myometrial cell line

Pulmonary surfactant proteins SP-A and SP-D are pattern recognition innate immune molecules. However, there is extrapulmonary existence, especially in the amniotic fluid and at the feto-maternal interface. There is sufficient evidence to suggest that SP-A and SP-D are involved in the initiation of labour. This is of great importance given that preterm birth is associated with increased mortality and morbidity. In this study, we investigated the effects of recombinant forms of SP-A and SP-D (rhSP-A and rhSP-D, the comprising of trimeric lectin domain) on contractile events in vitro, using a human myometrial cell line (ULTR) as an experimental model. Treatment with rhSP-A or rhSP-D increased the cell velocity, distance travelled and displacement by ULTR cells. rhSP-A and rhSP-D also affected the contractile response of ULTRs when grown on collagen matrices showing reduced surface area. We investigated this effect further by measuring contractility-associated protein (CAP) genes. Treatment with rhSP-A and rhSP-D induced expression of oxytocin receptor (OXTR) and connexin 43 (CX43). In addition, rhSP-A and rhSP-D were able to induce secretion of GROα and IL-8. rhSP-D also induced the expression of IL-6 and IL-6 Ra. We provide evidence that SP-A and SP-D play a key role in modulating events prior to labour by reconditioning the human myometrium and in inducing CAP genes and pro-inflammatory cytokines thus shifting the uterus from a quiescent state to a contractile one

Testing innovative strategies to reduce the social gradient in the uptake of bowel cancer screening: a programme of four qualitatively enhanced randomised controlled trial

Background: Bowel cancer screening reduces cancer-specific mortality. There is a socioeconomic gradient in the uptake of the English NHS Bowel Cancer Screening Programme (BCSP), which may lead to inequalities in cancer outcomes. Objective: To reduce socioeconomic inequalities in uptake of the NHS BCSP’s guaiac faecal occult blood test (gFOBt) without compromising uptake in any socioeconomic group. Design: Workstream 1 explored psychosocial determinants of non-uptake of gFOBt in focus groups and interviews. Workstream 2 developed and tested four theoretically based interventions: (1) ‘gist’ information, (2) a ‘narrative’ leaflet, (3) ‘general practice endorsement’ (GPE) and (4) an ‘enhanced reminder’ (ER). Workstream 3 comprised four national cluster randomised controlled trials (RCTs) of the cost-effectiveness of each intervention. Methods: Interventions were co-designed with user panels, user tested using interviews and focus groups, and piloted with postal questionnaires. RCTs compared ‘usual care’ (existing NHS BCSP invitations) with usual care plus each intervention. The four trials tested: (1) ‘gist’ leaflet (n = 163,525), (2) ‘narrative’ leaflet (n = 150,417), (3) GPE on the invitation letter (n = 265,434) and (4) ER (n = 168,480). Randomisation was based on day of mailing of the screening invitation. The Index of Multiple Deprivation (IMD) score associated with each individual’s home address was used as the marker of socioeconomic circumstances (SECs). Change in the socioeconomic gradient in uptake (interaction between treatment group and IMD quintile) was the primary outcome. Screening uptake was defined as the return of a gFOBt kit within 18 weeks of the invitation that led to a ‘definitive’ test result of either ‘normal’ (i.e. no further investigation required) or ‘abnormal’ (i.e. requiring referral for further testing). Difference in overall uptake was the secondary outcome. Results: The gist and narrative trials showed no effect on the SECs gradient or overall uptake (57.6% and 56.7%, respectively, compared with 57.3% and 58.5%, respectively, for usual care; all p-values > 0.05). GPE showed no effect on the gradient (p = 0.5) but increased overall uptake [58.2% vs. 57.5% in usual care, odds ratio (OR) = 1.07, 95% confidence interval (CI) 1.04 to 1.10; p < 0.0001]. ER showed a significant interaction with SECs (p = 0.005), with a stronger effect in the most deprived IMD quintile (14.1% vs. 13.3% in usual care, OR = 1.11, 95% CI 1.04 to 1.20; p = 0.003) than the least deprived (34.7% vs. 34.9% in usual care OR = 1.00, 95% CI 0.94 to 1.06; p = 0.98), and higher overall uptake (25.8% vs. 25.1% in usual care, OR = 1.07, 95% CI 1.03 to 1.11; p = 0.001). All interventions were inexpensive to provide. Limitations: In line with NHS policy, the gist and narrative leaflets supplemented rather than replaced existing NHS BCSP information. This may have undermined their effect. Conclusions: Enhanced reminder reduced the gradient and modestly increased overall uptake, whereas GPE increased overall uptake but did not reduce the gradient. Therefore, given their effectiveness and very low cost, the findings suggest that implementation of both by the NHS BCSP would be beneficial. The gist and narrative results highlight the challenge of achieving equitable delivery of the screening offer when all communication is written; the format is universal and informed decision-making mandates extensive medical information. Future work: Socioculturally tailored research to promote communication about screening with family and friends should be developed and evaluated. Trial registration: Current Controlled Trials ISRCTN74121020. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 5, No. 8. See the NIHR Journals Library website for further project information

A gyógyszeres terápia terhes fogbetegek

Pregnancy is a dynamic physiological state of a mother's body which has substantial effect on the health of the oral cavity. It is vital for pregnant patients to obtain sufficient oral health during the course of the pregnancy to maintain good health for both mother and fetus. Thorough knowledge of the mother's systemic and metabolic changes should be understood prior to administration of pharmacotherapeutic aided dental treatment, in addition to the gestational timings and changes undergone during this sensitive time. The dental profession should acknowledge the pharmacokinetics of the drug and assess the potential risks and benefits it may possess. This is clarified by using the FDA drug categories. Overall, a balance should be made to establish a way where dentists can provide safe, harmless dental treatment with no maternal risk compared to the risk of providing dental care. This is to ensure the most optimal care is provided and not to deprive the becoming of a mother to efficient and beneficial dental therapy.MSc/MAfogorvosangolVÁg

Attitudes of geneticists and patients toward incidental findings in Saudi Arabia

Background: In Middle East countries, including Saudi Arabia, 60%70% of all marriages occur between first cousins, leading to uniquely common genetic disorders compared to Western countries. The primary objective of this study is to investigate differences between the attitudes of genetics professionals and patients toward incidental findings identified through whole-genome sequencing (WGS)/whole exome sequencing (WES). Methodology: A mixed qualitative and quantitative cross-sectional study was done to assess the ethical dilemmas and challenges faced in providing genetic information to Saudi patients attending a genetics clinic. A webbased survey was used to interview the participants. A total of 50 subjects were enrolled in this cross-sectional study, including 20 genetics professionals (MG: medical geneticists and GC: genetic counselors) and 30 patients who were interviewed before and after Next-Generation Sequencing tests. Results: Among the total, 55% of genetic professionals disagreed on patients being provided with their genetic results and raw data, and they preferred focusing on actionable results that yield benefits such as medical treatment and disease prevention. However, the majority of patients (73.3%) were interested in receiving all the raw genomic data for themselves and their children, while 26.7% felt opposite. Conclusion: This study identified differences in the attitudes of genetics professionals and patients toward the reporting of incidental findings from WES/WGS. Overall, the results suggested that GCand MGshould be aware of variations in individual preferences and should respect the beliefs and preferences of their patients. [JBCGenetics 2019; 2(2.000): 116-121