The characterisation and regulation of T cell immune responses in psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis. It affects approximately 0.05% of the general population presenting as peripheral arthritis, axial disease or a combination of both. About 10% of patients with psoriasis suffer from PsA. Currently available therapies have limited efficacy with associated toxicity. PsA is therefore a common arthropathy for which novel therapies are urgently required. Our understanding of the role of the immune system in the pathogenesis of rheumatic disease has led to the development of specific targeted therapies. The identification of tumour necrosis factor alpha (TNFα) as a key player in the inflammatory response has been a major advance in the field of rheumatology. The effects of blocking this pro inflammatory molecule have resulted in dramatic clinical effects across the spectrum of rheumatic diseases. Unfortunately however there remain a proportion of non-responders and concerns have been raised surrounding the adverse effects of these therapies (Furst, Keystone et al. 2001). It is therefore important to continue to elucidate other key players in the inflammatory cascade that can be modified to achieve clinical response. A critical advance in understanding the immune system's role in driving inflammation has been the recognition of different functional subsets of T helper (Th) cells according to their cytokine profile. Techniques have evolved that enable us to achieve clarification of a true in vivo Th1 response by identifying cells in SF that spontaneously secrete IFNγ. In this thesis, spontaneously secreting cells were identified in SF of patients with active PsA. That such IFNγ expressing cells may have a pathogenic role in PsA is supported by the following observations: IFNγ is the prototype macrophage activator of TNFα that drives inflammation in psoriasis and PsA. IFNγ when tested as a potential treatment for psoriasis induced synovitis in a subset of patients. (O'Connell, Gerber et al. 1992). The injection of IFNγ into the skin induces hyperkeratosis (Fierlbeck, Rassner et al. 1990). Autologous Natural Killer T (NKT) cells, potent producers of IL-4 and IFNγ, are able to induce psoriasis in 'normal skin' grafted onto a SCID mouse (Nickoloff, Wrone- Smithetal. 1999). Those factors regulating the expression of IFNγ may therefore be of considerable interest as they may offer potential targets to modify Th1 responses in PsA. Cytokines such as interleukin 18 (IL-18) and interleukin 12 (IL-12) have been shown to regulate Th1 responses in animal models of arthritis (Leung, McInnes et al. 2000). Whether such cytokines are present and indeed induce inflammation in PsA is unknown. The first part of this thesis focuses on the characterisation of the predominant Th response in PsA and the identification of key regulatory cytokines such as IL-12 and IL-18 that may drive TNFα production and as such lead to inflammation. The presence of other regulatory cells capable of driving the inflammatory response was explored briefly. NKT cells are a subset of T cell, which secrete IFNγ and IL-4 depending on the predominant cytokine milieu (Hafner, Falk et al. 1999). A pathogenic role for NKT cells in psoriasis has been suggested. (Bonish, Jullien et al. 2000). The ability of synovial fluid mononuclear cells (SF MC) to proliferate and secrete TNFα in response to glycolipid presented to NK T cells was investigated. Although TNFα contributes directly to synovial inflammation, the blockade of TNFα does not protect completely against cartilage damage (Joosten, Helsen et al. 1999). IFNγ and IL- 17 have opposing effects on bone resorption. IFNγ inhibits bone resorption whereas IL-17 enhances resorption through the degradation or enhancement of TNF receptor associated factor 6 (TRAF6) respectively (Chabaud, Lubberts et al. 2001). The expression of IL-17 and the functional effects of this cytokine on MMP3 expression by fibroblasts were therefore studied as a final section in this thesis

A Miniaturized Laser Heterodyne Radiometer for a Global Ground-Based Column Carbon Monitoring Network

We present progress in the development of a passive, miniaturized Laser Heterodyne Radiometer (mini-LHR) that will measure key greenhouse gases (C02, CH4, CO) in the atmospheric column as well as their respective altitude profiles, and O2 for a measure of atmospheric pressure. Laser heterodyne radiometry is a spectroscopic method that borrows from radio receiver technology. In this technique, a weak incoming signal containing information of interest is mixed with a stronger signal (local oscillator) at a nearby frequency. In this case, the weak signal is sunlight that has undergone absorption by a trace gas of interest and the local oscillator is a distributive feedback (DFB) laser that is tuned to a wavelength near the absorption feature of the trace gas. Mixing the sunlight with the laser light, in a fast photoreceiver, results in a beat signal in the RF. The amplitude of the beat signal tracks the concentration of the trace gas in the atmospheric column. The mini-LHR operates in tandem with AERONET, a global network of more than 450 aerosol sensing instruments. This partnership simplifies the instrument design and provides an established global network into which the mini-LHR can rapidly expand. This network offers coverage in key arctic regions (not covered by OCO-2) where accelerated warming due to the release of CO2 and CH4 from thawing tundra and permafrost is a concern as well as an uninterrupted data record that will both bridge gaps in data sets and offer validation for key flight missions such as OCO-2, OCO-3, and ASCENDS. Currently, the only ground global network that routinely measures multiple greenhouse gases in the atmospheric column is TCCON (Total Column Carbon Observing Network) with 18 operational sites worldwide and two in the US. Cost and size of TCCON installations will limit the potential for expansion, We offer a low-cost $30Klunit) solution to supplement these measurements with the added benefit of an established aerosol optical depth measurement. Aerosols induce a radiative effect that is an important modulator of regional carbon cycles. Changes in the diffuse radiative flux fraction (DRF) due to aerosol loading have the potential to alter the terrestrial carbon exchange

Greenhouse Gas Concentration Data Recovery Algorithm for a Low Cost, Laser Heterodyne Radiometer

The goal of a coordinated effort between groups at GWU and NASA GSFC is the development of a low-cost, global, surface instrument network that continuously monitors three key carbon cycle gases in the atmospheric column: carbon dioxide (CO2), methane (CH4), carbon monoxide (CO), as well as oxygen (O2) for atmospheric pressure profiles. The network will implement a low-cost, miniaturized, laser heterodyne radiometer (mini-LHR) that has recently been developed at NASA Goddard Space Flight Center. This mini-LHR is designed to operate in tandem with the passive aerosol sensor currently used in AERONET (a well established network of more than 450 ground aerosol monitoring instruments worldwide), and could be rapidly deployed into this established global network. Laser heterodyne radiometry is a well-established technique for detecting weak signals that was adapted from radio receiver technology. Here, a weak light signal, that has undergone absorption by atmospheric components, is mixed with light from a distributed feedback (DFB) telecommunications laser on a single-mode optical fiber. The RF component of the signal is detected on a fast photoreceiver. Scanning the laser through an absorption feature in the infrared, results in a scanned heterodyne signal io the RF. Deconvolution of this signal through the retrieval algorithm allows for the extraction of altitude contributions to the column signal. The retrieval algorithm is based on a spectral simulation program, SpecSyn, developed at GWU for high-resolution infrared spectroscopies. Variations io pressure, temperature, composition, and refractive index through the atmosphere; that are all functions of latitude, longitude, time of day, altitude, etc.; are modeled using algorithms developed in the MODTRAN program developed in part by the US Air Force Research Laboratory. In these calculations the atmosphere is modeled as a series of spherically symmetric shells with boundaries specified at defined altitudes. Temperature, pressure, and species mixing ratios are defined at these boundaries. Between the boundaries, temperature is assumed to vary linearly with altitude while pressure (and thus gas density) vary exponentially. The observed spectrum at the LHR instrument will be the integration of the contributions along this light path. For any absorption measurement the signal at a particular spectral frequency is a linear combination of spectral line contributions from several species. For each species that might absorb in a spectral region, we have pre-calculated its contribution as a function of temperature and pressure. The integrated path absorption spectrum can then by calculated using the initial sun angle (from location, date, and time) and assumptions about pressure and temperature profiles from an atmospheric model. The modeled spectrum is iterated to match the experimental observation using standard multilinear regression techniques. In addition to the layer concentrations, the numerical technique also provides uncertainty estimates for these quantities as well as dependencies on assumptions inherent in the atmospheric models

Three Dimensional Quantification of Angiotensin II-Induced Murine Abdominal Aortic Aneurysms Using High Frequency Ultrasound

Abdominal aortic aneurysms (AAAs), a localized dilation of the vessel wall of 50% or more above normal, claims approximately 14,000 U.S. lives yearly due to aortic rupture. This commonly asymptomatic disease can only be treated by endovascular stent grafts or invasive surgery, usually after the AAA diameter reaches 5 cm. Because these treatment methods carry serious risk, stem cell therapy is being explored in order to provide a low risk option for managing smaller AAAs. To determine if stem cell therapy, once administered, could stabilize or reduce AAA growth, baseline 3D ultrasound measurements in a control group were first needed. High frequency ultrasound was used on apolipoprotein E-deficient (apoE-/-) mice given angiotensin II (AngII) from subcutaneously implanted osmotic mini pumps. This mouse model developed dissecting AAAs, containing a false and true lumen, which were clearly visualized and quantified using 3D ultrasound imaging. With this ultrasound technique, we found that aneurysm diameter, total volume, and false lumen volume all increased steadily over a period of 28 days once AAAs formed. These data suggest our noninvasive, 3D ultrasound technique can be used to monitor the progression of aneurysms that may be delayed once stem cell therapy is administered

Nonlinear Optical Microscopy of Murine Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by dilation and weakening of the vessel wall. AAA rupture is responsible for approximately 14,000 deaths annually in the United States [1]. Nonlinear optical (NLO) microscopy presents new possibilities for analyzing AAA tissue samples from murine models. Common NLO techniques are two-photon excitation fluorescence (TPEF), which detects the intrinsic autofluorescent properties of elastin, and second-harmonic generation (SHG), which is specific for collagen fibrils. Elastin and collagen, two major extracellular matrix components, help the aortic wall withstand internal pressure. Murine AAAs were created through 1) subcutaneous continuous systemic infusion of angiotensin II (AngII) in hyperlipidemic apolipoprotein E-deficient mice and 2) by intraluminal infusion of elastase (low 0.5 U/ml and high 25 U/ml concentrations) into the infrarenal aorta of rats [2]. We imaged aneurysmal and control tissue using TPEF and SHG and compared the resulting images to sections stained with standard elastin and collagen markers. TPEF images revealed disorganized elastin sheets and SHG images indicated collagen turnover after aneurysm formation. We quantified the relative degree of elastin degradation and collagen content in the aortic media within a user-defined area on sections stained with Verhoeff-van Gieson (VVG) or Masson’s trichrome (MTC), as well as on TPEF and SHG images. Our analysis with VVG-stained sections shows that elastin content in AAA tissue is significantly decreased by 64% in AngII models (P=0.02), by 34% in low concentration elastase models (P=0.07), and by 99% in high concentration elastase models (P=0.03), relative to control aortic tissue

Thinking like a man? The cultures of science

Culture includes science and science includes culture, but conflicts between the two traditions persist, often seen as clashes between interpretation and knowledge. One way of highlighting this false polarity has been to explore the gendered symbolism of science. Feminism has contributed to science studies and the critical interrogation of knowledge, aware that practical knowledge and scientific understanding have never been synonymous. Persisting notions of an underlying unity to scientific endeavour have often impeded rather than fostered the useful application of knowledge. This has been particularly evident in the recent rise of molecular biology, with its delusory dream of the total conquest of disease. It is equally prominent in evolutionary psychology, with its renewed attempts to depict the fundamental basis of sex differences. Wars over science have continued to intensify over the last decade, even as our knowledge of the political, economic and ideological significance of science funding and research has become ever more apparent

Operationalizing marketable blue carbon

The global carbon sequestration and avoided emissions potentially achieved via blue carbon is high (∼3% of annual global greenhouse gas emissions); however, it is limited by multidisciplinary and interacting uncertainties spanning the social, governance, financial, and technological dimensions. We compiled a transdisciplinary team of experts to elucidate these challenges and identify a way forward. Key actions to enhance blue carbon as a natural climate solution include improving policy and legal arrangements to ensure equitable sharing of benefits; improving stewardship by incorporating indigenous knowledge and values; clarifying property rights; improving financial approaches and accounting tools to incorporate co-benefits; developing technological solutions for measuring blue carbon sequestration at low cost; and resolving knowledge gaps regarding blue carbon cycles. Implementing these actions and operationalizing blue carbon will achieve measurable changes to atmospheric greenhouse gas concentrations, provide multiple co-benefits, and address national obligations associated with international agreements

The Binational/Crosscultural Health Enhancement Center

poster abstractThe Binational/Cross-Cultural Health Enhancement Center (BiCCHEC) fosters multidisciplinary research collaborations that address the biological, cultural, historical, legal, behavioral and demographic issues that impact the health status of communities where Latinos are born and where they live in Indiana. Since its inception, BiCCHEC projects have been multidisciplinary, 80% of the projects involve two or more IUPUI schools. BiCCHEC projects are also collaborative, 70% of the projects have one or more community partners. BiCCHEC researchers have also established a strong commitment to teaching and service, actively involving students in research (25% of current projects are student led) and servicelearning activities, developing exchange programs through our partnerships and providing direct health services in community organized events. Signature center funds have been utilized to fund internal pilot projects. The current poster will highlight four of those projects that have received pilot funding from signature center funds and have resulted in external grant applications or have already received funding, or have resulted in peer reviewed-publications. These projects are considered representative of BiCCHEC’s activities, because of their collaborative, multidisciplinary and community-based nature and include: • Study on oral health disparities using community-based participatory research • Study on the attitudes regarding children with disabilities, beliefs regarding death, coping skills and supports used during bereavement in communities in Indiana and rural Mexico • Building of a bi-national research partnership for healthful eating and diabetes prevention among Mexican and Mexican-American children • Study on emigration and return migration in 20th Century Mexico: Across the border and back again • Study on the effects of migrants' acculturation on oral health and diet in Indianapolis and Tala, Jaliscco using social network theor

At-risk registers integrated into primary care to stop asthma crises in the UK (ARRISA-UK): study protocol for a pragmatic, cluster randomised trial with nested health economic and process evaluations

Background: Despite effective treatments and long-standing management guidelines, there are approximately 1400 hospital admissions for asthma weekly in the United Kingdom (UK), many of which could be avoided. In our previous research, a secondary analysis of the intervention (ARRISA) suggested an improvement in the management of at-risk asthma patients in primary care. ARRISA involved identifying individuals at risk of adverse asthma events, flagging their electronic health records, training practice staff to develop and implement practice-wide processes of care when alerted by the flag, plus motivational reminders. We now seek to determine the effectiveness and cost-effectiveness of ARRISA in reducing asthma-related crisis events. Methods: We are undertaking a pragmatic, two-arm, multicentre, cluster randomised controlled trial, plus health economic and process evaluation. We will randomise 270 primary care practices from throughout the UK covering over 10,000 registered patients with ‘at-risk asthma’ identified according to a validated algorithm. Staff in practices randomised to the intervention will complete two 45-min eLearning modules (an individually completed module giving background to ARRISA and a group-completed module to develop practice-wide pathways of care) plus a 30-min webinar with other practices. On completion of training at-risk patients’ records will be coded so that a flag appears whenever their record is accessed. Practices will receive a phone call at 4 weeks and a reminder video at 6 weeks and 6 months. Control practices will continue to provide usual care. We will extract anonymised routine patient data from primary care records (with linkage to secondary care data) to determine the percentage of at-risk patients with an asthma-related crisis event (accident and emergency attendances, hospitalisations and deaths) after 12 months (primary outcome). We will also capture the time to crisis event, all-cause hospitalisations, asthma control and any changes in practice asthma management for at-risk and all patients with asthma. Cost-effectiveness analysis and mixed-methods process evaluations will also be conducted. Discussion: This study is novel in terms of using a practice-wide intervention to target and engage with patients at risk from their asthma and is innovative in the use of routinely captured data with record linkage to obtain trial outcomes. Trial registration: ISRCTN95472706. Registered on 5 December 2014

Underpinning Sustainable Vector Control through Informed Insecticide Resistance Management

Background: There has been rapid scale-up of malaria vector control in the last ten years. Both of the primary control strategies, long-lasting pyrethroid treated nets and indoor residual spraying, rely on the use of a limited number of insecticides. Insecticide resistance, as measured by bioassay, has rapidly increased in prevalence and has come to the forefront as an issue that needs to be addressed to maintain the sustainability of malaria control and the drive to elimination. Zambia’s programme reported high levels of resistance to the insecticides it used in 2010, and, as a result, increased its investment in resistance monitoring to support informed resistance management decisions. Methodology/Principal Findings: A country-wide survey on insecticide resistance in Zambian malaria vectors was performed using WHO bioassays to detect resistant phenotypes. Molecular techniques were used to detect target-site mutations and microarray to detect metabolic resistance mechanisms. Anopheles gambiae s.s. was resistant to pyrethroids,DDT and carbamates, with potential organophosphate resistance in one population. The resistant phenotypes were conferred by both target-site and metabolic mechanisms. Anopheles funestus s.s. was largely resistant to pyrethroids and carbamates, with potential resistance to DDT in two locations. The resistant phenotypes were conferred by elevated levels of cytochrome p450s. Conclusions/Significance: Currently, the Zambia National Malaria Control Centre is using these results to inform their vector control strategy. The methods employed here can serve as a template to all malaria-endemic countries striving to create a sustainable insecticide resistance management pla