Molecular genetic and epigenetic analysis of osteoarthritis

PhD ThesisOsteoarthritis (OA) is a common degenerative disease of synovial joints that principally affects older individuals. The genetic architecture of OA is highly complex, with heterogeneous pathological pathways converging on a common end phenotype characterised by the painful loss of articular cartilage. In this study, I investigated both genetic and epigenetic aspects of the OA disease process. The genetic investigation focused on the functional analysis of a female hip OA association signal that was discovered in the arcOGEN study, marked by the single nucleotide polymorphism (SNP) rs4836732. The signal surpasses the genome-wide significance threshold, with p = 6.11x10-10. The signal encompasses only two other SNPs that have a high degree of linkage disequilibrium (LD) with rs4836732. Functional studies using luciferase reporter assays, electrophoretic mobility shift assays (EMSAs) and a range of transformed cell lines did not identify any differential allelic activity between SNP alleles, but did identify differential EMSA banding patterns for the C allele of rs4836732 when compared to the T allele, suggestive of differential protein complex binding dependent on the allele present at rs4836732. Subsequent investigations focused on three genes in the immediate vicinity of the association signal: ASTN2, PAPPA and TRIM32. All three genes were expressed in cartilage, synovium and fat pad from OA patients, though none displayed differential allelic expression correlating with rs4836732 genotype in these tissues. This lack of positive evidence in end-stage disease tissue may be indicative of the association signal mediating risk during joint development or growth. Of the three genes, PAPPA was deemed the most likely candidate to have a functional affect in joint development. Knock-down of the gene in mesenchymal stem cells revealed that PAPPA is required for osteogenic and chondrogenic differentiation, providing support ii for further investigation of this gene. My second line of investigation focused on OA epigenetics, specifically on subgroups of hip and knee OA patients who displayed altered cartilage methylation of inflammatory genes when analysed by high-density CpG methylation array. As part of this study, I developed pyrosequencing assays to determine the inflammatory subgroup of new patient cartilage samples, negating the need for a high-density array. I also further interrogated the inflammatory status of the patients, analysing serum markers of systemic inflammation and gathering biometric data to ascertain the primary cause of inflammation, with a focus on the metabolic status of patients in relation to body fat. Interestingly, no systemic differences in inflammation, circulating leptin or BMI were observed. This suggests the elevated inflammatory status may be local to the synovial joint, as opposed to being secondary to increased systemic inflammation. Overall, the two investigation routes that I have pursued further emphasise the heterogeneous nature of OA. They also highlight the importance of patient stratification for OA research and provide platforms to improve our comprehension of this debilitating disease.William Harker Foundatio

Checking the Threads of an IUCD

In 2014/15, slightly more than a third of women using sexual and reproductive health services for contraception (excluding those who were only seeking advice) were using some type of long-acting reversible contraceptive or LARC (Health and Social Care Information Centre, 2015). In general practice, despite an initiative to encourage prescription of LARCs, the proportion of women using these methods may well be lower (Arrowsmith et al., 2014). Many of the women using LARCs will have been fitted with an intrauterine contraceptive device (IUCD): either a levonorgestrel-releasing intrauterine system or a copper intrauterine device

Taking female genital swabs

Just over 8 per cent of young people aged 15 to 24 years, out of 1.7 million tested in 2013, tested positive for genital Chlamydia trachomatis (Public Health England, 2014a). This sexually transmitted bacterial infection is asymptomatic in 70 per cent of women, although it may cause vaginal discharge, post-coital bleeding, dysuria, lower abdominal pain, deep dyspareunia and cervicitis (Lazero, 2013). More than 50 per cent of men with chlamydia are asymptomatic when tested in community settings. Two-thirds of the sexual partners of people diagnosed with chlamydia also have this infection. If untreated, chlamydia infection can persist for years (Public Health England, 2014b). Complications of untreated chlamydia, such as infertility and pelvic inflammatory disease, are estimated to cost more than £100 million a year (Lazero, 2013)

Giving a contraceptive injection

Women who have decided to use the contraceptive injection as their method of contraception need to attend for regular repeat injections, at specific intervals depending on which medication is used (FSRH, 2015). The prescribing clinician will have ensured that the woman meets the UK Medical Eligibility Criteria for the injection (RCOG, 2015), and she will have already received counselling about the advantages and disadvantages of the method. You must adhere to the Nursing and Midwifery Council’s Standards for Medicines Management (2010), which in this case includes awareness of the UK Medical Eligibility Criteria for the contraceptive injection (RCOG, 2015)

Effects of Music Therapy on Stressed Postpartum Mothers Trying to Breastfeed

Objective: Evaluate the effect of music therapy and breast milk production on postpartum mothers with anxiety. Design: Quasi-experimental, comparative Setting: HaysMed OB Participants: Postpartum mothers who gave birth at HaysMed who are planning on breastfeeding. Methods: Participants will fill out a chart of how long and how often the baby is feeding. Mothers will also fill out a survey about their anxiety levels throughout the process of breastfeeding. Results: Pending results and data collectio

Activating the Innate Immune Response by Utilizing Macrophages as a Defense for Immunosuppressed Individuals and COVID-19

The activation of the innate immune response by utilizing Interferon-Gamma to activate macrophages will provide for immunosuppressed individuals an additional treatment option for COVID-19

BIOL 404- The Effects of Dioxin-like Polychlorinated Biphenyls (PCBs) on the Development of Myeloid Suppressor Cells

Polychlorinated biphenyls (PCBs) are a man-made organic compound consisting of two phenyl rings connected by a single bond, with any number of chlorine molecules occupying positions around the rings. They are most commonly used as a dielectric and coolant fluid in electrical generators and transformers. Manufacture has declined drastically since the 1970s in America due to their exertion of estrogen-mimicking effects in the body, although they continue to persist in harmful concentrations in the environment. PCBs are endocrine-disrupting, and through estrogenic or anti-estrogenic effects have been shown to increase breast cancer risk by changing gene expression in several genes common to the formation of breast tissue cancer cells, including IGF-1, which fuels all stages of cancer growth. We intend to test cells in vitro for additional sensitivities to the estrogen mimicking effects of PCB 138 and PCB 153. This will hopefully elucidate the mechanistic effects of PCBs on the endocrine system

Royal Society education outreach training course evaluation

This evaluation explores the perceptions of Royal Society Research Fellows to education outreach and the drivers that stimulate them to undertake it. It also reports on the successes and challenges of a pilot training course for Research Fellows on education outreach. The pilot scheme was organised by The Training Group and covered a wide variety of topics including; theoretical information about learning styles and the UK education system, discussion activities for the Research Fellows, and activities to brainstorm and test potential outreach activities.The evaluation used a variety of data collection methods to elicit the views of participating Research Fellows and Royal Society staff and was conducted by the Science Communication Unit at the University of the West of England, Bristol. The report presents the indicators for impacts from education outreach, the methods and toolkit for undertaking the evaluation, and the results and recommendations from the pilot scheme

A Global Climatological Model of Extreme Geomagnetic Field Fluctuations

This paper presents a multi-parameter global statistical model of extreme horizontal geomagnetic field fluctuations (dBH/dt), which are a useful input to models assessing the risk of geomagnetically induced currents in ground infrastructure. Generalised Pareto (GP) distributions were fitted to 1-minute measurements of |dBH/dt| from 125 magnetometers (with an average of 28 years of data per site) and return levels (RL) predicted for return periods (RP) between 5 and 500 years. Analytical functions characterise the profiles of maximum-likelihood GP model parameters and the derived RLs as a function of corrected geomagnetic latitude, λ. A sharp peak in both the GP shape parameter and the RLs is observed at |λ|=53° in both hemispheres, indicating a sharp equatorward limit of the auroral electrojet region. RLs also increase strongly in the dayside region poleward of the polar cusp (|λ|>75°) for RPs > 100 years. We describe how the GP model may be further refined by modelling the probability of occurrences of |dBH/dt| exceeding the 99.97th percentile as a function of month, magnetic local time, and the direction of the field fluctuation, dBH , and demonstrate that these patterns of occurrence align closely to known patterns of auroral substorm onsets, ULF Pc5 wave activity, and (storm) sudden commencement impacts. Changes in the occurrence probability profiles with the interplanetary magnetic field (IMF) orientation reveal further details of the nature of the ionospheric currents driving extreme |dBH/dt| fluctuations, such as the changing location of the polar cusp and seasonal variations explained by the Russell-McPherron effect

The evaluation of training oral and maxillofacial trainees in head and neck cancer doctor-patient communication using the Patient Concerns Inventory.

AbstractHead and neck cancer has a significant impact on a patient’s health related quality of life (HRQOL). The head and neck specific Patient Concerns Inventory (PCI-HN) has been utilised to enhance doctor-patient dialogue in routine consultations. To date there has been no formal training for oral and maxillofacial surgery (OMFS) surgical trainees in the use of the PCI-HN in consultations. The aim of the study was to evaluate training for OMFS surgical trainees in the use of the PCI-HN, using simulated follow-up HNC consultations, in order to improve doctor-patient communication skills.Material and methodsTen oral and maxillofacial surgical trainees completed actor simulated HNC consultations before and after training. A study-specific mark scheme was developed based on the ComOn-Coaching rating scales and used to score the doctor-patient interaction. A group debrief afterwards explored the trainee’s experiences of the training and consultations. ResultsAll trainees showed an improvement in doctor-patient communication scores following their training. Overall, the six participants who were Specialty registrars, year 3 (ST3) or above, scored higher, than the four Specialty registrars, year 1-2 (ST1-2). The scores were higher if fewer PCI-HN items were discussed (3-4). The most frequently avoided PCI-HN items were intimacy and relationships. The trainees considered that their training was useful for organising their consultations and for providing holistic care. ConclusionAlthough training improved surgeon-patient communication, further evaluation is required with a larger number of trainees and actual consultations in clinic.<br/