Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents.

Tooth replacement for partially dentate elders: a willingness-to-pay analysis

Objectives: The primary aim of this study was to investigate partially dentate elders’ willingness-to-pay (WTP) for two different tooth replacement strategies: using Removable Partial Dentures (RPDs) and, functionally orientated treatment (SDA). The secondary aim was to measure the same patient group’s WTP for dental implants. Methods: Patients who had completed a previous RCT comparing two tooth replacement strategies (RPDs and SDA) were recruited. 59 patients were asked to indicate their WTP for treatment to replace missing teeth in a number of hypothetical scenarios using the payment card method of contingency evaluation coupled to different costs. Data were collected on patients’ social class, longest held occupation, income levels and social circumstances. Results: The median age for the patient sample was 72.0 years (IQR: 71-75 years). Patients who had previously been provided with RPDs indicated that their WTP for this treatment strategy was significantly higher than those patients who had received SDA treatment (Mann-Whitney U Test: p<0.001). This group were also WTP a higher price for SDA treatment than those patients who had previously been treated according to this modality (Mann-Whitney U Test: p=0.005). The results indicated that patients’ age was not correlated with WTP but both social class and current income levels were significantly correlated (Spearman’s rank correlation: p<0.05). Patients in both treatment groups exhibited llittle WTP for dental implant treatment with a median price recorded which was lower than either RPD or SDA treatment. Conclusions: Amongst this patient cohort previous treatment experience had a strong influence on WTP as did social class and current income levels. The patients’ WTP indicated that they did not value dental implants over simpler forms of tooth replacement such as RPDs or a SDA approach.

Economics of Non-Communicable Diseases in Indonesia

The Economics of Non-Communicable Diseases in Indonesia provides new data on the economic burden of NCDs in the country, and puts it in perspective by drawing a comparison with India and China. With this new addition to the series on the economics of NCDs, the World Economic Forum aims to advance the understanding of the expected economic output loss at the country level, particularly in countries in economic and epidemiological transition. The evidence presented provides a starting point in reorienting the dialogue on investing in healthy living and NCD prevention in Indonesia towards the view that a healthy population is an important factor for sustainable growth.

Occlusal considerations in periodontics

Periodontal disease does not directly affect the occluding surfaces of teeth, consequently some may find a section on periodontics a surprising inclusion. Trauma from the occlusion, however, has been linked with periodontal disease for many years. Karolyi published his pioneering paper, in 1901 'Beobachtungen uber Pyorrhoea alveolaris' (occlusal stress and 'alveolar pyorrhoea'). (1) However, despite extensive research over many decades, the role of occlusion in the aetiology and pathogenesis of inflammatory periodontitis is still not completely understood.

Tooth replacement for partially dentate elders: a willingness-to-pay analysis

Objectives: The primary aim of this study was to investigate partially dentate elders’ willingness-to-pay (WTP) for two different tooth replacement strategies: using Removable Partial Dentures (RPDs) and, functionally orientated treatment (SDA). The secondary aim was to measure the same patient group’s WTP for dental implants.Methods: Patients who had completed a previous RCT comparing two tooth replacement strategies (RPDs and SDA) were recruited. 59 patients were asked to indicate their WTP for treatment to replace missing teeth in a number of hypothetical scenarios using the payment card method of contingency evaluation coupled to different costs. Data were collected on patients’ social class, longest held occupation, income levels and social circumstances.Results: The median age for the patient sample was 72.0 years (IQR: 71-75 years). Patients who had previously been provided with RPDs indicated that their WTP for this treatment strategy was significantly higher than those patients who had received SDA treatment (Mann-Whitney U Test: p<0.001). This group were also WTP a higher price for SDA treatment than those patients who had previously been treated according to this modality (Mann-Whitney U Test: p=0.005). The results indicated that patients’ age was not correlated with WTP but both social class and current income levels were significantly correlated (Spearman’s rank correlation: p<0.05).Patients in both treatment groups exhibited llittle WTP for dental implant treatment with a median price recorded which was lower than either RPD or SDA treatment.Conclusions: Amongst this patient cohort previous treatment experience had a strong influence on WTP as did social class and current income levels. The patients’ WTP indicated that they did not value dental implants over simpler forms of tooth replacement such as RPDs or a SDA approach.

Targeting the complement system for the management of retinal inflammatory and degenerative diseases

The retina, an immune privileged tissue, has specialized immune defense mechanisms against noxious insults that may exist in diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), uveoretinitis and glaucoma. The defense system consists of retinal innate immune cells (including microglia, perivascular macrophages, and a small population of dendritic cells) and the complement system. Under normal aging conditions, retinal innate immune cells and the complement system undergo a low-grade activation (parainflammation) which is important for retinal homeostasis. In disease states such as AMD and DR, the parainflammatory response is dysregulated and develops into detrimental chronic inflammation. Complement activation in the retina is an important part of chronic inflammation and may contribute to retinal pathology in these disease states. Here, we review the evidence that supports the role of uncontrolled or dysregulated complement activation in various retinal degenerative and angiogenic conditions. We also discuss current strategies that are used to develop complement-based therapies for retinal diseases such as AMD. The potential benefits of complement inhibition in DR, uveoretinitis and glaucoma are also discussed, as well as the need for further research to better understand the mechanisms of complement-mediated retinal damage in these disease states.

ASYN and tau interaction : new drug target for neurodegenerative diseases

Tese de doutoramento, Bioquímica (Biotecnologia), Universidade de Lisboa, Faculdade de Ciências, 2014

Towards the therapeutic use of regulatory T cells for the treatment of human autoimmune diseases

Tese de doutoramento, Medicina (Imunologia Clínica), Universidade de Lisboa, Faculdade de Medicina, 2016

Active design of tooth profiles using parabolic curve as the line of action

This paper proposes a method for the design of gear tooth profiles using parabolic curve as its line of action. A mathematical model, including the equation of the line of action, the equation of the tooth profile, and the equation of the conjugate tooth profile, is developed based on the meshing theory. The equation of undercutting condition is derived from the model. The influences of the two design parameters, that present the size (or shape) of the parabolic curve relative to the gear size, on the shape of tooth profiles and on the contact ratio are also studied through the design of an example drive. The strength, including the contact and the bending stresses, of the gear drive designed by using the proposed method is analyzed by an FEA simulation. A comparison of the above characteristics of the gear drive designed with the involute gear drive is also carried out in this work. The results confirm that the proposed design method is more flexible to control the shape of the tooth profile by changing the parameters of the parabola.

Occupational exposure to environmental tobacco smoke in hospitality venues: are genetic- or proteomics-based biomarkers predictive of respiratory diseases?

Environmental tobacco smoke (ETS) is recognized as an occupational hazard in the hospitality industry. Although Portuguese legislation banned smoking in most indoor public spaces, it is still allowed in some restaurants/bars, representing a potential risk to the workers’ health, particularly for chronic respiratory diseases. The aims of this work were to characterize biomarkers of early genetic effects and to disclose proteomic signatures associated to occupational exposure to ETS and with potential to predict respiratory diseases development. A detailed lifestyle survey and clinical evaluation (including spirometry) were performed in 81 workers from Lisbon restaurants. ETS exposure was assessed through the level of PM 2.5 in indoor air and the urinary level of cotinine. The plasma samples were immunodepleted and analysed by 2D-SDSPAGE followed by in-gel digestion and LC-MS/MS. DNA lesions and chromosome damage were analysed innlymphocytes and in exfoliated buccal cells from 19 cigarette smokers, 29 involuntary smokers, and 33 non-smokers not exposed to tobacco smoke. Also, the DNA repair capacity was evaluated using an ex vivo challenge comet assay with an alkylating agent (EMS). All workers were considered healthy and recorded normal lung function. Interestingly, following 2D-DIGE-MS (MALDI-TOF/TOF), 61 plasma proteins were found differentially expressed in ETS-exposed subjects, including 38 involved in metabolism, acute-phase respiratory inflammation, and immune or vascular functions. On the other hand, the involuntary smokers showed neither an increased level of DNA/chromosome damage on lymphocytes nor an increased number of micronuclei in buccal cells, when compared to non-exposed non-smokers. Noteworthy, lymphocytes challenge with EMS resulted in a significantly lower level of DNA breaks in ETS-exposed as compared to non-exposed workers (P<0.0001) suggestive of an adaptive response elicited by the previous exposure to low levels of ETS. Overall, changes in proteome may be promising early biomarkers of exposure to ETS. Likewise, alterations of the DNA repair competence observed upon ETS exposure deserves to be further understood. Work supported by Fundação Calouste Gulbenkian, ACSS and FCT/Polyannual Funding Program.

Sexual functioning in people with stable chronic diseases

Backgound - In developed countries people are living longer and the incidence of chronic disease is increasing. Chronic disease and its treatments can have a negative impact on sexual functioning and sexual satisfaction. Aim of study - To explore and to compare sexual function and sexual satisfaction in people with stable chronic diseases.

Development of CO-releasing molecular for the treatment of inflammatory diseases

Dissertation presented to obtain a Ph.D. degree (Doutoramento) in Chemistry at the Instituto de Tecnologia Quimica e Biol6gica da Universidade Nova de Lisboa

Disposable immunosensor using a simple method for oriented antibody immobilization for label-free real-time detection of an oxidative stress biomarker implicated in cancer diseases

This work proposes a novel approach for a suitable orientation of antibodies (Ab) on an immunosensing platform, applied here to the determination of 8-hydroxy-2′-deoxyguanosine (8OHdG), a biomarker of oxidative stress that has been associated to chronic diseases, such as cancer. The anti-8OHdG was bound to an amine modified gold support through its Fc region after activation of its carboxylic functions. Non-oriented approaches of Ab binding to the platform were tested in parallel, in order to show that the presented methodology favored Ab/Ag affinity and immunodetection of the antigen. The immunosensor design was evaluated by quartz-crystal microbalance with dissipation, atomic force microscopy, electrochemical impedance spectroscopy (EIS) and square-wave voltammetry. EIS was also a suitable technique to follow the analytical behavior of the device against 8OHdG. The affinity binding between 8OHdG and the antibody immobilized in the gold modified platform increased the charge transfer resistance across the electrochemical set-up. The observed behavior was linear from 0.02 to 7.0 ng/mL of 8OHdG concentrations. The interference from glucose, urea and creatinine was found negligible. An attempt of application to synthetic samples was also successfully conducted. Overall, the presented approach enabled the production of suitably oriented Abs over a gold platform by means of a much simpler process than other oriented-Ab binding approaches described in the literature, as far as we know, and was successful in terms of analytical features and sample application.