Regional, disease specific patterns of smoking-attributable mortality in 2000

Background: Smoking has been causally associated with increased mortality from several diseases, and has increased considerably in many developing countries in the past few decades. Mortality attributable to smoking in the year 2000 was estimated for adult males and females, including estimates by age and for specific diseases in 14 epidemiological subregions of the world. Methods: Lung cancer mortality was used as an indirect marker of the accumulated hazard of smoking. Never-smoker lung cancer mortality was estimated based on the household use of coal with poor ventilation. Estimates of mortality caused by smoking were made for lung cancer, upper aerodigestive cancer, all other cancers, chronic obstructive pulmonary disease ( COPD), other respiratory diseases, cardiovascular diseases, and selected other medical causes. Estimates were limited to ages 30 years and above. Results: In 2000, an estimated 4.83 million premature deaths in the world were attributable to smoking, 2.41 million in developing countries and 2.43 million in industrialised countries. There were 3.84 million male deaths and 1.00 million female deaths attributable to smoking. 2.69 million smoking attributable deaths were between the ages of 30 - 69 years, and 2.14 million were 70 years of age and above. The leading causes of death from smoking in industrialised regions were cardiovascular diseases ( 1.02 million deaths), lung cancer (0.52 million deaths), and COPD (0.31 million deaths), and in the developing world cardiovascular diseases (0.67 million deaths), COPD (0.65 million deaths), and lung cancer (0.33 million deaths). The share of male and female deaths and younger and older adult deaths, and of various diseases in total smoking attributable deaths exhibited large inter-regional heterogeneity, especially in the developing world. Conclusions: Smoking was an important cause of global mortality in 2000, affecting a large number of diseases. Age, sex, and disease patterns of smoking-caused mortality varied greatly across regions, due to both historical and current smoking patterns, and the presence of other risk factors that affect background mortality from specific diseases.

The short-term effects of air pollution on hospital admissions in four Australian cities

Background. This paper examines the short-term health effects of air pollution on daily hospital admissions in Australian cities (those considered comprise more than 50% of the Australian population) for the period 1996-99. Methods: The study used a similar protocol to overseas studies and derived single city and pooled estimates using different statistical approaches to assess the accuracy of the results. Results: There was little difference between the results derived from the different statistical approaches for cardiovascular admissions, while in those for respiratory admissions there were differences. For three of the four cities (for the other the results were positive but not significant), fine particles (measured by nephelometry - bsp) and nitrogen dioxide (NO2) have a significant impact on cardiovascular admissions (for total cardiac admissions, RR=1.0856 for a one-unit increase in bsp (10(-4). m(-1)), RR=1.0023 for a 1 ppb increase in NO2). For three of the four cities (for the other, the results were negative and significant), fine particles, NO2 and ozone have a significant impact on respiratory admissions (for total elderly respiratory admissions, RR=1.0552 per 1 unit (10(-4).m(-1)) increase in bsp, RR=1.0027 per 1ppb increase in NO2, RR=10014 per 1 ppb increase in ozone for elderly asthma and COPD admissions). In all analyses the particle and NO2 impacts appear to be related. Conclusions: Similar to overseas studies, air pollution has an impact on hospital admissions in Australian cities, but there can be significant differences between cities.

S100A8 chemotactic protein is abundantly increased, but only a minor contributor to LPS-induced, steroid resistant neutrophilic lung inflammation in vivo

Neutrophilic lung inflammation is an essential component of host defense against diverse eukaryotic and prokaryotic pathogens, but in chronic inflammatory lung diseases, such as chronic obstructive lung disease (COPD), severe asthma, cystic fibrosis, and bronchiolitis, it may damage the host. Glucocorticosteroids are widely used in these conditions and in their infectious exacerbations; however, the clinical efficacy of steroids is disputed. In this study, we used a proteomic approach to identify molecules contributing to neutrophilic inflammation induced by transnasal administration of lipopolysaccharide (LPS) that were also resistant to the potent glucocorticosteroid dexamethasone (Dex). We confirmed that Dex was biologically active at both the transcript (suppression of GM-CSF and TNFalpha transcripts) and protein levels (induction of lipocortin) and used 2D-PAGE/MALDI-TOF to generate global expression profiles, identifying six LPS-induced proteins that were Dex resistant. Of these, S100A8, a candidate neutrophil chemotactic factor, was profiled in detail. Steroid refractory S100A8 expression was highly abundant, transcriptionally regulated, secreted into lung lavage fluid and immunohistochemically localized to tissue infiltrating neutrophils. However, in marked contrast to other vascular beds, neutralizing antibodies to S100A8 had only a weak anti-neutrophil recruitment effect and antibodies against the related S100A9 were ineffective. These data highlight the need for extensive in vivo profiling of proteomically identified candidate molecules and demonstrates that S100A8, despite its abundance, resistance to steroids and known chemotactic activity, is unlikely to be an important determinant of LPS-induced neutrophilic lung inflammation in vivo.

Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects

Background: Inflammatory markers are increased in chronic obstructive pulmonary disease ( COPD) and are hypothesised to play an important part in muscle dysfunction and exercise intolerance. Methods: The Health Aging and Body Composition ( Health ABC) study is a prospective observational cohort of well functioning individuals aged 70 - 79 years. A cross sectional analysis of the baseline data was conducted to examine the association between inflammatory markers and ventilatory limitation, muscle strength, and exercise capacity. These associations were compared in participants with and without obstructive lung disease ( OLD). Results: Of the 3075 participants enrolled in the Health ABC cohort, OLD was identified by spirometric testing in 268 participants and 2005 participants had normal spirometric results. Of the participants with OLD, 35%, 38%, and 27% participants had mild, moderate, and severe OLD, respectively. Participants with OLD had lower quadriceps strength (102.5 Nm v 108.9 Nm, p = 0.02), lower maximum inspiratory pressure (64.7 cm H2O v 74.2 cm H2O, p< 0.0001), higher systemic interleukin (IL)-6 levels (2.6 pg/ml v 2.2 pg/ml, p< 0.0001), and higher C-reactive protein (CRP) levels (3.5 mg/l v 2.5 mg/l, p< 0.0001) than those with normal spirometry. In participants with OLD and those with normal spirometry, forced expiratory volume in 1 second (FEV1) was associated with IL-6 ( adjusted regression coefficients (beta) = -5.3 (95% CI -9.1 to -1.5) and -3.1 (95% CI -4.3 to -1.9), respectively). IL-6 and TNF were also associated with quadriceps strength among participants with OLD and those with normal spirometry (beta = -6.4 (95% CI -12.8 to -0.03) and -3.4 (95% CI -5.4 to -1.3), respectively, for IL-6 and beta = -10.1 (95% CI -18.7 to -1.5) and -3.8 (95% CI -7 to -0.6), respectively, for TNF). IL-6, quadriceps strength, and maximum inspiratory pressures were independent predictors of reduced exercise capacity in both groups. Conclusions: In well functioning elderly subjects with or without OLD, IL-6 is associated with reduced FEV1, quadriceps strength, and exercise capacity.

Measuring the global burden of disease and epidemiological transitions: 2002-2030

Any planning process for health development ought to be based on a thorough understanding of the health needs of the population. This should be sufficiently comprehensive to include the causes of premature death and of disability, as well as the major risk factors that underlie disease and injury. To be truly useful to inform health-policy debates, such an assessment is needed across a large number of diseases, injuries and risk factors, in order to guide prioritization. The results of the original Global Burden of Disease Study and, particularly, those of its 2000-2002 update provide a conceptual and methodological framework to quantify and compare the health of populations using a summary measure of both mortality and disability: the disability-adjusted life-year (DALY). Globally, it appears that about 5 6 million deaths occur each year, 10. 5 million (almost all in poor countries) in children. Of the child deaths, about one-fifth result from perinatal causes such as birth asphyxia and birth trauma, and only slightly less from lower respiratory infections. Annually, diarrhoeal diseases kill over 1.5 million children, and malaria, measles and HIV/AIDS each claim between 500,000 and 800,000 children. HIV/AIDS is the fourth leading cause of death world-wide (2.9 million deaths) and the leading cause in Africa. The top three causes of death globally are ischaemic heart disease (7.2 million deaths), stroke (5.5 million) and lower respiratory diseases (3.9 million). Chronic obstructive lung diseases (COPD) cause almost as many deaths as HIV/AIDS (2.7 million). The leading causes of DALY, on the other hand, include causes that are common at young ages [perinatal conditions (7. 1 % of global DALY), lower respiratory infections (6.7%), and diarrhoeal diseases (4.7%)] as well as depression (4.1%). Ischaemic heart disease and stroke rank sixth and seventh, retrospectively, as causes of global disease burden, followed by road traffic accidents, malaria and tuberculosis. Projections to 2030 indicate that, although these major vascular diseases will remain leading causes of global disease burden, with HIV/AIDS the leading cause, diarrhoeal diseases and lower respiratory infections will be outranked by COPD, in part reflecting the projected increases in death and disability from tobacco use.

Identifying the scope for savings at inpatient episode level:an illustration applying DEA to chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by a largely irreversible obstruction of the airways, and is one of the leading causes of chronic morbidity and mortality worldwide. This paper illustrates the use of Data Envelopment Analysis (DEA) to assess the potential for cost savings at COPD inpatient episode level. The analysis uses the length of stay of each episode as a surrogate for expenditure on that episode while allowing for the medical condition of the patient and the quality of care received. We find substantial possible reductions in length of stay which would translate to cost savings. The paper also explores differences both between hospitals and between care teams within hospitals so that cost efficient protocols of treatment can be identified and disseminated.

Validity of the portable piko-6 spirometer used for screening obstructive airway diseases in community pharmacy practice

Background: Obstructive airway diseases (OADs) are among the leading causes of morbidity and mortality worldwide. Shortness of breath (SOB) is the main symptom associated with OADs. International guidelines from the Global Initiative for Chronic Lung Disease (GOLD) and the Global Initiative for Asthma (GINA) have recommended spirometry as an indispensable tool for the diagnosis of asthma and chronic obstructive pulmonary diseases (COPD), but spirometry is rarely used in family practice. Simple and reliable diagnostic tools are necessary for screening community patients with onset of OADs for timely management. Purpose: This thesis examined screening utility of the PiKo-6 forced expiratory volume in one second (pFEV₁) , in six second (pFEV₆), and the pRatio ( pFEV₁/pFEV₆) in SOB patients for OADs in community pharmacy settings. FEV₆ has recently been suggested an excellent surrogate for Forced Vital Capacity (FVC), which requires maximum exhalation of the lungs. Methods: Patients with SOB symptoms who were prescribed pulmonary inhalers, by their family physicians, were recruited via community pharmacies. Trained pharmacists collected two PiKo-6 tests to assess the repeatability of the PiKo-6 device. All patients performed laboratory spirometry ( FEV₁, FVC and FEV₁/FVC) to obtain physician diagnosis of their OADs. The results of the PiKo-6 spirometer and laboratory spirometer were compared. In addition, the PiKo-6 pRatio and laboratory FEV₁/FVC were assessed against physician diagnosed COPD. Results: Sixty three patients volunteered to perform the PiKo-6 spirometry. Of these, 52.4 % were men (age 53.9 ± 15.3 years; BMI 31.9 ± 7.40 kg/m2). Repeated testing with pFEV₁, pFEV6 and pRatio correlated significantly (within correlation, r = 0.835, p-Value≤ 0.05 ; 0.872, p- Value≤ 0.05; and 0.664, p-Value≤ 0.05). In addition, pFEV₁, pFEV6 and pRatio correlated significantly with FEV₁, FVC and FEV₁/FVC, respectively (between correlation = 0.630, p- Value≤ 0.05 ; 0.660, p-Value≤ 0.05 and 0.580, p-Value≤ 0.05). The cut-off value corresponding to the greatest sum of sensitivity and specificity of pRatio for physician-diagnosed COPD was <0.80, the sensitivity and specificity were 84 % and 50%, respectively. Conclusions The portable PiKo-6 correlates moderately well with the standard spirometry, when delivered by community pharmacists to patients with OADs. The PiKo-6 spirometer may play a role in screening patients suspected of having an OAD in community pharmacies that may benefit from early physician diagnosis and appropriate management.

What We Mean When We Talk About Adherence In Respiratory Medicine

Funding acknowledgements The Respiratory Effectiveness Group (REG; www.effectivenessevaluation.org) supported the Expert Adherence Panel Meeting at which many of the concepts presented in this paper were first discussed. REG also supported the manuscript submission costs. AD, EvG and MdB have received funding from the European Community’s 7th Framework (FP7/2007-2013) under grant agreement n°282593.

What We Mean When We Talk About Adherence In Respiratory Medicine

Funding acknowledgements The Respiratory Effectiveness Group (REG; www.effectivenessevaluation.org) supported the Expert Adherence Panel Meeting at which many of the concepts presented in this paper were first discussed. REG also supported the manuscript submission costs. AD, EvG and MdB have received funding from the European Community’s 7th Framework (FP7/2007-2013) under grant agreement n°282593.

Symptom burden and its relationship to functional performance in patients with chronic obstructive pulmonary disease

The aim of this study was to explore symptom burden and its relationship to functional performance in patients with COPD. A descriptive, cross-sectional, correlational survey design was used and a sample of 214 patients with COPD. The sample was recruited from patients attending one of the major teaching hospitals in Dublin. Symptom burden was measured using the Memorial Symptom Assessment Scale (MSAS), and the functional performance was measured using the Functional Performance Inventory-Short Form (FPISF). Findings revealed that participants experienced a median of 13 symptoms. The most burdensome symptoms were shortness of breath, lack of energy, difficulty sleeping, worrying, dry mouth, feeling nervous, feeling irritable, and feeling sad. Participants with very severe COPD had the greatest symptom burden, followed by those with severe COPD, moderate COPD, and mild COPD. Symptom burden was higher for the psychological symptoms compared to the physical symptoms. Participants with mild COPD had the highest functional performance, followed by those with moderate COPD, very severe COPD, and severe COPD. Twenty symptoms were negatively correlated with overall functional performance, indicating that high symptom burden for those symptoms was associated with low overall functional performance. Moderate, negative, statistically significant correlations were found between the total symptom burden and overall functional performance, physical symptom burden and overall functional performance and psychological symptom burden and overall functional performance. A negative linear relationship was found between total symptom burden and overall functional performance among all stages of COPD except the mild group. No relationship was found between total symptom burden and overall functional performance for the moderate group. Healthcare professionals need to broaden the clinical and research assessment of physical and psychological symptoms in COPD; alleviating the burden of these symptoms may promote improved functional performance.

STRUCTURAL AND FUNCTIONAL CORRELATES OF EXERCISE VENTILATORY INEFFICIENCY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS WITH MILD-TO-MODERATE SPIROMETRIC ABNORMALITIES

Background: Individuals with chronic obstructive pulmonary disease (COPD) have higher than normal ventilatory equivalents for carbon dioxide (VE/VCO2) during exercise. There is growing evidence that emphysema on thoracic computed tomography (CT) scans is associated with poor exercise capacity in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that emphysema is an underlying cause of microvascular dysfunction and ventilatory inefficiency, which in turn contributes to reduced exercise capacity. We expected ventilatory inefficiency to be associated with a) the extent of emphysema; b) lower diffusing capacity for carbon monoxide; c) a reduced pulmonary blood flow response to exercise; and d) reduced exercise capacity. Methods: In a cross-sectional study, 19 subjects with mild-to-moderate COPD (mean ± SD FEV1= 82 ± 13% predicted, 12 GOLD grade 1) and 26 age-, sex-, and activity-matched controls underwent a ramp-incremental symptom-limited exercise test on a cycle ergometer. Ventilatory inefficiency was assessed by the minimum VE/VCO2 value (nadir). A subset of subjects also completed repeated constant work rate exercise bouts with non-invasive measurements of pulmonary blood flow. Emphysema was quantified as the percentage of attenuation areas below -950 Housefield Units on CT scans. An electronic scoresheet was used to keep track of emphysema sub-types. Results: COPD subjects typically had centrilobular emphysema (76.8 ± 10.1% of total emphysema) in the upper lobes (upper/lower lobe ratio= 0.82 ± 0.04). They had lower peak oxygen uptake (VO2), higher VE/VCO2 nadir and greater dyspnea scores than controls (p<0.05). Lower peak O2 and worse dyspnea were found in COPD subjects with VE/VCO2 nadirs ≥ 30. COPD subjects had blunted increases in pulmonary blood flow from rest to iso-VO2 exercise (p<0.05). Higher VE/VCO2 nadir in COPD subjects correlated with emphysema severity (r= 0.63), which in turn correlated with reduced lung diffusing capacity (r= -0.72) and blunted changes in pulmonary blood flow from rest to exercise (r= -0.69) (p<0.01). Conclusions: Ventilation “wasted” in emphysematous areas is associated with reduced exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (gas transfer) to a key clinical outcome (reduced exercise capacity) in COPD patients with modest spirometric abnormalities.

Exercit@rt mobile : monitorização da reabilitação respiratória na DPOC

A prevalência estimada da Doença Pulmonar Obstrutiva Crónica (DPOC) em Portugal é de 14,2% para indivíduos com idade superior a 45 anos (cerca de 800.000 indivíduos), sendo mais prevalente no sexo masculino (Observatório Nacional das Doenças Respiratórias, 2014). Com o aparecimento de soluções baseadas em novas modalidades de eHealth e mHealth surgiram novas formas de acompanhamento e monitorização das doenças crónicas, nomeadamente da DPOC. É neste contexto que foi desenvolvida a aplicação mobile Exercit@rt, em parceria com a Escola Superior de Saúde da Universidade de Aveiro e em continuidade com outros estudos do MCMM anteriormente desenvolvidos. A aplicação permite monitorizar, em tempo real, através da utilização de um oxímetro Bluetooth, os níveis de batimento cardíaco e saturação de oxigénio dos pacientes com DPOC. Com esta aplicação os pacientes podem realizar diversos exercícios de fisioterapia respiratória assim como atividades físicas de vida diária que podem ser monitorizadas, georreferenciadas e avaliadas. Para além do desenvolvimento da aplicação mobile, a presente investigação integrou ainda uma etapa de validação que contou com a participação de dez pacientes com doenças do foro respiratório – cinco utilizadores que utilizam/têm smartphone (UTS) e cinco utilizadores não utilizam/não têm smartphone (NUNTS). A cada um destes foram propostas tarefas a realizar na aplicação mobile, estando previsto que a aplicação estivesse apta para qualquer participante. A totalidade dos participantes reconheceu a utilidade da aplicação no controlo da sua doença.

Altération de la régénération musculaire dans la maladie pulmonaire obstructive chronique

Altération de la régénération musculaire dans la maladie pulmonaire obstructive chronique. La maladie pulmonaire obstructive chronique (MPOC) est caractérisée par une obstruction bronchique irréversible et progressive. L’atrophie musculaire périphérique y est fréquente et a un impact négatif sur la capacité fonctionnelle et la survie des sujets atteints. Toutefois, on ignore si une altération du processus de régénération musculaire est un processus ayant cours dans l’atrophie musculaire périphérique. Le but de la présente thèse était donc d’étudier les cellules satellites, principales cellules responsables de la régénération musculaire dans les muscles périphériques de patients ayant une MPOC. Dans un premier temps, nous avons évalué l’historique de réplication du tissu musculaire et la sénescence des cellules satellites. Les changements morphologiques ayant lieu dans le muscle au cours de la progression de la maladie rendent le muscle plus susceptible aux dommages, induisant un raccourcissement prématuré des télomères. Un raccourcissement des télomères chez les sujets ayant une MPOC avec atrophie est concomitant avec une augmentation du nombre de cellules satellites sénescentes et de l’épuisement du potentiel de régénération compromettant le maintien de la masse musculaire chez ces sujets. Dans un deuxième et troisième temps, nous avons étudié les étapes amenant une cellule satellite vers une cellule musculaire dans les muscles périphériques et respiratoires de patients ayant une MPOC comparativement à des sujets contrôles. Les cellules satellites sont impliquées dans la réparation du tissu musculaire. Dans les cellules satellites provenant des sujets ayant une MPOC, une altération de la prolifération et de la différentiation a été observée. Ces résultats sont compatibles avec une altération de la régénération musculaire pouvant conduire à l’atrophie musculaire dans la MPOC. Le quatrième volet de ce projet s’intéressait à l’impact d’un entraînement en résistance sur l’activité des cellules satellites et le rôle joué par la myostatine dans ce contexte. La littérature montre que l’exercice en résistance est bien toléré et aide les patients ayant une MPOC à retrouver une meilleure qualité de vie. Cependant, il semble qu’ils n’y répondent pas tous aussi bien que les sujets contrôles. La capacité de réponse des cellules satellites à un entraînement en résistance semble inadéquate, suggérant ainsi un défaut de leur activation. Dans la dernière étude de cette thèse, nous avons voulu évaluer l’impact de l’inflammation systémique en étudiant SAA1, une protéine de phase aiguë et p21, une protéine du cycle cellulaire dans la dégradation des protéines des cellules musculaires. Les liens de causalité entre l’affection primaire et les différentes comorbidités demeurent nébuleux dans la MPOC. SAA1 et p21 sont augmentés dans les muscles squelettiques des patients ayant une MPOC et par ailleurs, SAA1 est capable d’induire la dégradation des protéines musculaires. Cette thèse expose les premiers éléments impliquant l’altération de la régénération musculaire avec la dysfonction musculaire observée chez les patients ayant une MPOC. Ces résultats vont certainement contribuer au développement de nouvelles thérapies et stratégies d’intervention dans le but d’améliorer la qualité de vie des personnes atteintes d’une MPOC. En somme, les travaux effectués dans le cadre de la présente thèse montrent que plusieurs mécanismes agissent de concert avec l’inactivité physique afin d’induire le phénotype dysfonctionnel dans les muscles des patients ayant une MPOC.

Treino de músculos inspiratórios em indivíduos saudáveis: estudo randomizado controlado

Introdução – O treino dos músculos inspiratórios (TMI) surge como uma intervenção importante na população com doença pulmonar obstrutiva crónica (DPOC), mas com interesse crescente na população saudável. No entanto, não existem estudos suficientes que comprovem se o treino dos músculos inspiratórios se traduz também numa melhoria da capacidade aeróbia objetivada no consumo de oxigénio (VO2). Assim, a relação entre o TMI e os seus resultados no indivíduo saudável carece de estudo que comprove os efeitos reais do treino. Considerou-se, pelo anteriormente exposto, pertinente a realização de um estudo de investigação na população saudável que permitisse avaliar em que medida um programa de TMI induz alterações na força muscular inspiratória e na capacidade aeróbia. Métodos e análise – A amostra foi constituída por indivíduos saudáveis (n=19) com idades compreendidas entre os 18 e 21 anos que realizam exercício físico regularmente (≥3 vezes por semana ou ≥4h por semana). A capacidade aeróbia foi estimada através do Teste de Ebbeling e a força dos músculos inspiratórios foi medida pela pressão inspiratória máxima (PIM) obtida num dinamómetro específico (MicroRPM®), em dois momentos distintos (pré e pós-treino). A referida amostra foi dividida aleatoriamente em dois grupos (n=9 no grupo experimental e n=10 no grupo de controlo). O grupo experimental (GE) foi submetido a um TMI de alta intensidade (≥50% Pi,máx), enquanto o grupo de controlo (GC) não foi sujeito a qualquer intervenção. O TMI foi realizado através do PowerBreathe Classic® Level 1 e Level 2, que fornece uma pressão consistente e específica para a força muscular inspiratória, independentemente do fluxo inspiratório do indivíduo. Conclusões – Após o treino verificou-se um aumento de 37% na PIM do GE, enquanto o GC apresentou uma melhoria de 7%. Na comparação intragrupos, ambos os grupos aumentaram significativamente tanto a PIM como o VO2 (p<0,05). Já na comparação intergrupos, a diferença foi significativa para a PIM (p=0,000), mas não para o VO2. Serão necessários mais estudos no sentido de concluir e avaliar em que condições o TMI produz alterações na capacidade aeróbia.

Comparison of the modes of action of Apremilast and Roflumilast

The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.