Healthcare systems were surprised by a viral disease named COVID19. In all countries, worse or be... more Healthcare systems were surprised by a viral disease named COVID19. In all countries, worse or better all governments and health systems had to rapidly focus on saving the lives of the infected ones and screen and diagnose many suspected patients. As fast as possible, hospitals tried to improve their intensive care response, make beds available for COVID19 patients, and stop non-urgent activity to decrease COVID19 patient exposure and also free resources.
United around COVID19 management, government, healthcare administrators, healthcare professionals... more United around COVID19 management, government, healthcare administrators, healthcare professionals, professional associations, patients, pharmaceutical companies, and all sorts of businesses contributed to the combat of the pandemic, but also to suppress other patient needs. What all these stakeholders did and are doing together is overtaking barriers to patient-centered healthcare innovation. The pandemic had the advantage of focusing all stakeholders in increasing value to the patient through the unique way that value can be generated collaboration and patient centricity. All of the following cases are revenant to increase value for the patients and value for the overall system even after the COVID19 pandemic.
To determine the effects of acetylcholine and spermineNONOate--a NO donor--on RBC membrane and ox... more To determine the effects of acetylcholine and spermineNONOate--a NO donor--on RBC membrane and oxygen carrying properties. Aliquots of venous blood from eleven healthy subjects were incubated with ACh 10(-3) M, ACh 10(-5) M, spermineNONOate 10(-5) M and spermineNONOate 10(-4) M. The following parameters were determined: erythrocyte aggregation and deformability, hematocrit, plasma pH, osmolality, K(+), Na(+), Ca(2+) concentrations, hemoglobin, oxyhemoglobin, carboxyhemoglobin and methemoglobin concentrations, oxygen saturation of hemoglobin, oxygen and carbon dioxide partial pressures and p50. In presence of ACh there is an increase of erythrocyte deformability, decrease of erythrocyte aggregation, plasma pH, K(+) and Na(+) concentration, increase of Ca(2+) concentration and p50. In presence of spermineNONOate there is an increase of erythrocyte deformability, plasma pH, decrease of Na(+) and Ca(2+) concentration, increase of metHb concentration and decrease of p50. Acetylcholine an...
To determine the effects of choline on red blood cell membrane properties and NO metabolism. Aliq... more To determine the effects of choline on red blood cell membrane properties and NO metabolism. Aliquots of venous blood from eleven healthy subjects were incubated in vitro with choline concentrations 10(-10) to 10(-3) M. The following parameters were determined: erythrocyte deformability, aggregation and membrane lipid fluidity, plasma K+, Na+, Ca2+, total blood haemoglobin and methemoglobin concentrations. Additionally, plasma and intra-erythrocyte nitrites concentrations were measured. Choline increases erythrocyte deformability at lower shear stresses, decreases erythrocyte aggregation, increases membrane lipid fluidity, and decreases of Na+ plasma concentrations. We also find an increase of nitrites concentration both in the plasma and in the intra-erythrocyte compartment. Choline induces changes on erythrocyte membrane properties, Na+ plasma concentration, and NO metabolites concentrations.
Urocortin (Ucn) is an endogenous cardioprotective agent that protects against the damaging effect... more Urocortin (Ucn) is an endogenous cardioprotective agent that protects against the damaging effects of ischemia and reperfusion injury in vitro and in vivo. We have found that the mechanism of action of Ucn involves both acute activation of specific target molecules, and using Affymetrix (Santa Clara, CA) gene chip technology, altered gene expression of different end effector molecules. Here, from our gene chip data, we show that after a 24 h exposure to Ucn, there was a specific increase in mRNA and protein levels of the protein kinase C epsilon (PKCε) isozyme in primary rat cardiomyocytes compared with untreated cells and in the Langendorff perfused ex vivo heart. Furthermore, a short 10 min exposure of these cells to Ucn caused a specific translocation/activation of PKCε in vitro and in the Langendorff perfused ex vivo heart. The importance of the PKCε isozyme in cardioprotection and its relationship to cardioprotection produced by Ucn was assessed using PKCε-specific inhibitor peptides. The inhibitor peptide, when introduced into cardiomyocytes, caused an increase in apoptotic cell death compared with control peptide after ischemia and reperfusion. When the inhibitor peptide was present with Ucn, the cardioprotective effect of Ucn was lost. This loss of cardioprotection by Ucn was also seen in whole hearts from PKCε knockout mice. These findings indicate that the cardioprotective effect of Ucn is dependent upon PKCε. Key words: ischemia • protein kinase C epsilon • apoptosis • mitochondria rocortin (Ucn) is a small 40-amino acid corticotrophin-releasing hormone (CRH) family member, which has potent protective properties against ischemia and reperfusion injury in the heart (1-3). The cardioprotection produced by Ucn can be seen in primary cardiomyocytes in vitro, on the Langendorff perfused rat heart ex vivo, and in the intact animal in vivo (1-5). U
Acetylcholine has been detected in human blood. Acetylcholine receptors and acetylcholinesterase ... more Acetylcholine has been detected in human blood. Acetylcholine receptors and acetylcholinesterase are present in erythrocyte membranes. We tested the acetylcholine and choline effects on nitric oxide metabolites (NOx), namely nitrites and nitrates, and observed if they are dependent on interactions with muscarinic receptors and acetylcholinesterase. Human erythrocyte suspensions were incubated with acetylcholine and choline in the absence or presence of 10 microM atropine or 10 microM velnacrine maleate. The nitrite and nitrate concentrations were determined by the Griess method. Acetylcholine or choline increased NOx control concentrations (P <0.001). The nitrite concentrations decreased in the presence of atropine or velnacrine maleate (P <0.03). The nitrate concentrations only decreased when velnacrine maleate was incubated with acetylcholine or choline (10 microM, P <0.03). These results demonstrated that acetylcholine and choline modulate nitric oxide metabolites on erythrocytes and this effect is mediated by interactions with erythrocyte membrane muscarinic receptors and membrane enzyme acetylcholinesterase. A hypothesis for the signal transduction mechanism has been discussed for acetylcholinesterase and muscarinic receptor (M1) participation.
Background: The access to healthcare and treatment by rheumatoid arthritis (RA) patients, particu... more Background: The access to healthcare and treatment by rheumatoid arthritis (RA) patients, particularly to biologics, differs significantly among European countries. We aimed to explore the views and experiences of Portuguese healthcare stakeholders on key barriers which limit the access to treatment, and ultimately to biologics, by RA patients and to find potential solutions (leverage points) to overcome the identified barriers. Methods: This was a qualitative research consisting of semi-structured face-to-face interviews with key stakeholders in RA framework. Thirty four individuals from eight groups of stakeholders were interviewed: rural and urban general practitioners (GPs), rheumatologists, hospital managers, hospital pharmacists, budget holders, representatives from the Portuguese Rheumatology Society and the RA Patient Association. Interviews were conducted between May and June 2011. Conventional content analysis with research triangulation was used. Results: The key barriers identified were related to the accessibility to primary healthcare services, difficulties in RA diagnosis among GPs, inefficient referral to secondary healthcare and controlled process of biologics prescription in public hospitals. The leverage points identified included the improvement of epidemiological and clinical knowledge about RA in Portugal, a better understanding of the disease among patients and GPs, the clarification of biologics benefits among budget holders and a raised awareness of the current treatment guidelines. In order to further address the leverage points, the following key initiatives were proposed: optimization of RA national registry; dissemination of information on rheumatic symptoms in primary care facilities and among the general public; increase interaction between rheumatologists and GPs through clinical discussions of successfully treated patients or workshops; broader utilization of disease diagnosis and monitoring tools, such as DAS28, and implementation of hospital-based research to collect real-world data. Conclusions: Most of the key barriers limiting the access to treatment, including biologics, in RA in Portugal are upstream of rheumatology practice. Our findings suggest that future actions should be focused on the primary care level to improve referral to rheumatologists. In addition, the collection of real-world data seems essential to characterise the RA population, to improve disease management and to increase compliance with current treatment guidelines.
Early diagnosis and treatment of Rheumatoid Arthritis (RA) and axial Spondylarthritis (axial SpA)... more Early diagnosis and treatment of Rheumatoid Arthritis (RA) and axial Spondylarthritis (axial SpA) can limit the impact of disease outcomes. This study evaluated the effectiveness of a referral program on the identification of patients with RA and axial SpA. This was an observational, prospective, randomized (by clusters) study conducted in Portugal to evaluate the impact of the implementation of a set of referral support actions (RSA). The study was divided in two sub-studies, the RA sub-study and the axial SpA sub-study. 28 participating primary care units were randomly (by clusters) assigned to RSA or control group (with no intervention). Both RSA and control groups identified and referred patients with suspected RA or axial SpA to the rheumatology unit of the reference hospital. The primary objective was to evaluate the correct diagnosis of RA or axial SpA cases confirmed by the rheumatologist of the reference hospital. RA-Substudy: A total of 340 patients were recruited (144 in ...
NO is present in the blood at 10(-7) M under physiological conditions, but at concentrations high... more NO is present in the blood at 10(-7) M under physiological conditions, but at concentrations higher than 10(-6) M during inflammatory disease states. The aim of this study was to characterize what are the effects of these different NO concentrations on erythrocyte structural and functional properties. Blood was collected from eleven healthy men and incubated with SpermineNONOate in order to expose it during incubation time to NO concentrations between 10(-7) M and 10(-3) M. We measured erythrocyte aggregation and deformability, membrane lipid peroxidation and fluidity, p50, hemoglobin, oxyhemoglobin, methemoglobin concentrations and plasma pH, pO(2), pCO(2), Na(+), K(+) and Ca(2+). When blood was exposed to NO 10(-7) M erythrocyte deformability increase and p50 decrease. In presence of NO 10(-5) M lipid fluidity and p50 decrease. When blood was exposed to NO 10(-3) M methemoglobin concentration increase and erythrocyte deformability and p50 decrease but membrane fluidity and lipid p...
Previous studies have documented structural and functional changes induced by ethanol-erythrocyte... more Previous studies have documented structural and functional changes induced by ethanol-erythrocyte membrane interaction. In order to perform an in vitro study on the effect of different ethanol concentrations on erythrocyte hemorheologic properties, blood samples were collected from 21 male donors at the Hospital of Santa Maria. Whole blood aliquots were incubated with ethanol solutions of rising concentrations. The following parameters were measured: erythrocyte aggregation, haemoglobin, carboxyhaemoglobin and methaemoglobin concentrations, hematocrit, plasma osmolality and erythrocyte membrane fluidity (fluorescence polarisation probes TMA-DPH and DPH). With ethanol blood concentrations of 45 mM a rise in plasma osmolality (0.352 Osm/kg H2O vs 0.310 Osm/kg H2O; p < 0.001) was verified. With 67 mM concentration a decrease of erythrocyte aggregation (11.03 vs 12.81; p < 0.05) and an increase in plasma osmolality (0.380 Osm/kg H2O vs 0.310 Osm/kg H2O; p < 0.001) were obtained...
To compare health care utilization between duloxetine initiators and pregabalin initiators among ... more To compare health care utilization between duloxetine initiators and pregabalin initiators among fibromyalgia patients in a real-world setting. METHODS: A retrospective cohort study was conducted based on a US national commercial health claims database (2006-2009). Fibromyalgia patients who initiated duloxetine or pregabalin in 2008, age 18 to 64, and maintained continuous health insurance coverage one year before and one year after initiation were as
The pathways which regulate resolution of inflammation and contribute to positive remodeling of t... more The pathways which regulate resolution of inflammation and contribute to positive remodeling of the myocardium following injury are poorly understood. Here we show that protein kinase C epsilon (PKC) cooperates with the phosphatase calcineurin (CN) to potentiate induction of cardioprotective gene expression while suppressing expression of fibrosis markers. This was achieved by detailed analysis of the regulation of cyclooxygenase 2 (COX-2) expression as a marker gene and by using gene expression profiling to identify genes regulated by coexpression of CN-A␣/PKC in adult rat cardiac myofibroblasts (ARVFs) on a larger scale. GeneChip analysis of CN-A␣/PKC-coexpressing ARVFs showed that COX-2 provides a signature for wound healing and is associated with downregulation of fibrosis markers, including connective tissue growth factor (CTGF), fibronectin, and collagens Col1a1, Col3a1, Col6a3, Col11a1, Col12a1, and Col14a1, with concomitant upregulation of cardioprotection markers, including COX-2 itself, lipocalin 2 (LCN2), tissue inhibitor of metalloproteinase 1 (TIMP-1), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). In primary rat cardiomyocyte cultures Toll-like receptor 4 (TLR4) agonist-or PKC/CNdependent COX-2 induction occurred in coresident fibroblasts and was blocked by selective inhibition of CN or PKC ␣/ or elimination of fibroblasts. Furthermore, ectopic expression of PKC and CN in ARVFs showed that the effects on COX-2 expression are mediated by specific NFAT sites within the COX-2 promoter as confirmed by site-directed mutagenesis and chromatin immunoprecipitation (ChIP). Therefore, PKC may negatively regulate adverse myocardial remodeling by cooperating with CN to downregulate fibrosis and induce transcription of cardioprotective wound healing genes, including COX-2.
Despite the widespread availability of biologics across Europe, rheumatoid arthritis (RA) patient... more Despite the widespread availability of biologics across Europe, rheumatoid arthritis (RA) patients&amp;amp;amp;amp;#39; access to these drugs differs significantly among countries. To compare the proportion of RA patients treated with biologics across Europe and investigate the factors that most influence it, with focus on the Portuguese case, reportedly with low access rates to biologics. The biologics&amp;amp;amp;amp;#39; market was characterized for 15 selected European countries. Variables potentially influencing patients&amp;amp;amp;amp;#39; access to biologics (PAB) in RA were also collected, including demographic, disease, economic, funding and biologics&amp;amp;amp;amp;#39; market-related data. A multivariable regression model identified the factors that best explain PAB. Based on these determinants, a cluster analysis was performed to group the countries with most similar behaviour regarding PAB allowing the evaluation of Portugal&amp;amp;amp;amp;#39;s relative position among these countries. The regression model (R(2) = 0.953) indicated that PAB in selected countries is explained mostly by its gross domestic product (GDP) per capita, the usage of methotrexate (MTX) and the biologics&amp;amp;amp;amp;#39; distribution channel. Current MTX usage in Portugal shows similarity with practice from UK, France, Germany or Spain 5 years before, explaining why PAB in Portugal stood at 7% in 2010, 12 percentage points below the average of selected countries. Variations in RA PAB were found across selected countries with Portugal showing the lowest proportion. GDP per capita, biologics distribution channel and consumption of MTX appear to be the best explanatory factors for these fluctuations in European countries.
Previous studies have documented structural and functional changes induced by ethanol-erythrocyte... more Previous studies have documented structural and functional changes induced by ethanol-erythrocyte membrane interaction. In order to perform an in vitro study on the effect of different ethanol concentrations on erythrocyte hemorheologic properties, blood samples were collected from 21 male donors at the Hospital of Santa Maria. Whole blood aliquots were incubated with ethanol solutions of rising concentrations. The following parameters were measured: erythrocyte aggregation, haemoglobin, carboxyhaemoglobin and methaemoglobin concentrations, hematocrit, plasma osmolality and erythrocyte membrane fluidity (fluorescence polarisation probes TMA-DPH and DPH). With ethanol blood concentrations of 45 mM a rise in plasma osmolality (0.352 Osm/kg H2O vs 0.310 Osm/kg H2O; p &amp;amp;lt; 0.001) was verified. With 67 mM concentration a decrease of erythrocyte aggregation (11.03 vs 12.81; p &amp;amp;lt; 0.05) and an increase in plasma osmolality (0.380 Osm/kg H2O vs 0.310 Osm/kg H2O; p &amp;amp;lt; 0.001) were obtained. In conclusion, ethanol only changes erythrocyte aggregation for a concentration of 67 mM. These data could lead to future changes in therapeutic approaches to situations such as alcoholic coma.
NO is present in the blood at 10 −7 M under physiological conditions, but at concentrations highe... more NO is present in the blood at 10 −7 M under physiological conditions, but at concentrations higher than 10 −6 M during inflammatory disease states. The aim of this study was to characterize what are the effects of these different NO concentrations on erythrocyte structural and functional properties. Blood was collected from eleven healthy men and incubated with SpermineNONOate in order to expose it during incubation time to NO concentrations between 10 −7 M and 10 −3 M. We measured erythrocyte aggregation and deformability, membrane lipid peroxidation and fluidity, p50, hemoglobin, oxyhemoglobin, methemoglobin concentrations and plasma pH, pO2, pCO2, Na + , K + and Ca 2+. When blood was exposed to NO 10 −7 M erythrocyte deformability increase and p50 decrease. In presence of NO 10 −5 M lipid fluidity and p50 decrease. When blood was exposed to NO 10 −3 M methemoglobin concentration increase and erythrocyte deformability and p50 decrease but membrane fluidity and lipid peroxidation were similar to control. In conclusion, dependent of NO concentrations there is different effects on erythrocytes structural and functional properties.
Healthcare systems were surprised by a viral disease named COVID19. In all countries, worse or be... more Healthcare systems were surprised by a viral disease named COVID19. In all countries, worse or better all governments and health systems had to rapidly focus on saving the lives of the infected ones and screen and diagnose many suspected patients. As fast as possible, hospitals tried to improve their intensive care response, make beds available for COVID19 patients, and stop non-urgent activity to decrease COVID19 patient exposure and also free resources.
United around COVID19 management, government, healthcare administrators, healthcare professionals... more United around COVID19 management, government, healthcare administrators, healthcare professionals, professional associations, patients, pharmaceutical companies, and all sorts of businesses contributed to the combat of the pandemic, but also to suppress other patient needs. What all these stakeholders did and are doing together is overtaking barriers to patient-centered healthcare innovation. The pandemic had the advantage of focusing all stakeholders in increasing value to the patient through the unique way that value can be generated collaboration and patient centricity. All of the following cases are revenant to increase value for the patients and value for the overall system even after the COVID19 pandemic.
To determine the effects of acetylcholine and spermineNONOate--a NO donor--on RBC membrane and ox... more To determine the effects of acetylcholine and spermineNONOate--a NO donor--on RBC membrane and oxygen carrying properties. Aliquots of venous blood from eleven healthy subjects were incubated with ACh 10(-3) M, ACh 10(-5) M, spermineNONOate 10(-5) M and spermineNONOate 10(-4) M. The following parameters were determined: erythrocyte aggregation and deformability, hematocrit, plasma pH, osmolality, K(+), Na(+), Ca(2+) concentrations, hemoglobin, oxyhemoglobin, carboxyhemoglobin and methemoglobin concentrations, oxygen saturation of hemoglobin, oxygen and carbon dioxide partial pressures and p50. In presence of ACh there is an increase of erythrocyte deformability, decrease of erythrocyte aggregation, plasma pH, K(+) and Na(+) concentration, increase of Ca(2+) concentration and p50. In presence of spermineNONOate there is an increase of erythrocyte deformability, plasma pH, decrease of Na(+) and Ca(2+) concentration, increase of metHb concentration and decrease of p50. Acetylcholine an...
To determine the effects of choline on red blood cell membrane properties and NO metabolism. Aliq... more To determine the effects of choline on red blood cell membrane properties and NO metabolism. Aliquots of venous blood from eleven healthy subjects were incubated in vitro with choline concentrations 10(-10) to 10(-3) M. The following parameters were determined: erythrocyte deformability, aggregation and membrane lipid fluidity, plasma K+, Na+, Ca2+, total blood haemoglobin and methemoglobin concentrations. Additionally, plasma and intra-erythrocyte nitrites concentrations were measured. Choline increases erythrocyte deformability at lower shear stresses, decreases erythrocyte aggregation, increases membrane lipid fluidity, and decreases of Na+ plasma concentrations. We also find an increase of nitrites concentration both in the plasma and in the intra-erythrocyte compartment. Choline induces changes on erythrocyte membrane properties, Na+ plasma concentration, and NO metabolites concentrations.
Urocortin (Ucn) is an endogenous cardioprotective agent that protects against the damaging effect... more Urocortin (Ucn) is an endogenous cardioprotective agent that protects against the damaging effects of ischemia and reperfusion injury in vitro and in vivo. We have found that the mechanism of action of Ucn involves both acute activation of specific target molecules, and using Affymetrix (Santa Clara, CA) gene chip technology, altered gene expression of different end effector molecules. Here, from our gene chip data, we show that after a 24 h exposure to Ucn, there was a specific increase in mRNA and protein levels of the protein kinase C epsilon (PKCε) isozyme in primary rat cardiomyocytes compared with untreated cells and in the Langendorff perfused ex vivo heart. Furthermore, a short 10 min exposure of these cells to Ucn caused a specific translocation/activation of PKCε in vitro and in the Langendorff perfused ex vivo heart. The importance of the PKCε isozyme in cardioprotection and its relationship to cardioprotection produced by Ucn was assessed using PKCε-specific inhibitor peptides. The inhibitor peptide, when introduced into cardiomyocytes, caused an increase in apoptotic cell death compared with control peptide after ischemia and reperfusion. When the inhibitor peptide was present with Ucn, the cardioprotective effect of Ucn was lost. This loss of cardioprotection by Ucn was also seen in whole hearts from PKCε knockout mice. These findings indicate that the cardioprotective effect of Ucn is dependent upon PKCε. Key words: ischemia • protein kinase C epsilon • apoptosis • mitochondria rocortin (Ucn) is a small 40-amino acid corticotrophin-releasing hormone (CRH) family member, which has potent protective properties against ischemia and reperfusion injury in the heart (1-3). The cardioprotection produced by Ucn can be seen in primary cardiomyocytes in vitro, on the Langendorff perfused rat heart ex vivo, and in the intact animal in vivo (1-5). U
Acetylcholine has been detected in human blood. Acetylcholine receptors and acetylcholinesterase ... more Acetylcholine has been detected in human blood. Acetylcholine receptors and acetylcholinesterase are present in erythrocyte membranes. We tested the acetylcholine and choline effects on nitric oxide metabolites (NOx), namely nitrites and nitrates, and observed if they are dependent on interactions with muscarinic receptors and acetylcholinesterase. Human erythrocyte suspensions were incubated with acetylcholine and choline in the absence or presence of 10 microM atropine or 10 microM velnacrine maleate. The nitrite and nitrate concentrations were determined by the Griess method. Acetylcholine or choline increased NOx control concentrations (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). The nitrite concentrations decreased in the presence of atropine or velnacrine maleate (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.03). The nitrate concentrations only decreased when velnacrine maleate was incubated with acetylcholine or choline (10 microM, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.03). These results demonstrated that acetylcholine and choline modulate nitric oxide metabolites on erythrocytes and this effect is mediated by interactions with erythrocyte membrane muscarinic receptors and membrane enzyme acetylcholinesterase. A hypothesis for the signal transduction mechanism has been discussed for acetylcholinesterase and muscarinic receptor (M1) participation.
Background: The access to healthcare and treatment by rheumatoid arthritis (RA) patients, particu... more Background: The access to healthcare and treatment by rheumatoid arthritis (RA) patients, particularly to biologics, differs significantly among European countries. We aimed to explore the views and experiences of Portuguese healthcare stakeholders on key barriers which limit the access to treatment, and ultimately to biologics, by RA patients and to find potential solutions (leverage points) to overcome the identified barriers. Methods: This was a qualitative research consisting of semi-structured face-to-face interviews with key stakeholders in RA framework. Thirty four individuals from eight groups of stakeholders were interviewed: rural and urban general practitioners (GPs), rheumatologists, hospital managers, hospital pharmacists, budget holders, representatives from the Portuguese Rheumatology Society and the RA Patient Association. Interviews were conducted between May and June 2011. Conventional content analysis with research triangulation was used. Results: The key barriers identified were related to the accessibility to primary healthcare services, difficulties in RA diagnosis among GPs, inefficient referral to secondary healthcare and controlled process of biologics prescription in public hospitals. The leverage points identified included the improvement of epidemiological and clinical knowledge about RA in Portugal, a better understanding of the disease among patients and GPs, the clarification of biologics benefits among budget holders and a raised awareness of the current treatment guidelines. In order to further address the leverage points, the following key initiatives were proposed: optimization of RA national registry; dissemination of information on rheumatic symptoms in primary care facilities and among the general public; increase interaction between rheumatologists and GPs through clinical discussions of successfully treated patients or workshops; broader utilization of disease diagnosis and monitoring tools, such as DAS28, and implementation of hospital-based research to collect real-world data. Conclusions: Most of the key barriers limiting the access to treatment, including biologics, in RA in Portugal are upstream of rheumatology practice. Our findings suggest that future actions should be focused on the primary care level to improve referral to rheumatologists. In addition, the collection of real-world data seems essential to characterise the RA population, to improve disease management and to increase compliance with current treatment guidelines.
Early diagnosis and treatment of Rheumatoid Arthritis (RA) and axial Spondylarthritis (axial SpA)... more Early diagnosis and treatment of Rheumatoid Arthritis (RA) and axial Spondylarthritis (axial SpA) can limit the impact of disease outcomes. This study evaluated the effectiveness of a referral program on the identification of patients with RA and axial SpA. This was an observational, prospective, randomized (by clusters) study conducted in Portugal to evaluate the impact of the implementation of a set of referral support actions (RSA). The study was divided in two sub-studies, the RA sub-study and the axial SpA sub-study. 28 participating primary care units were randomly (by clusters) assigned to RSA or control group (with no intervention). Both RSA and control groups identified and referred patients with suspected RA or axial SpA to the rheumatology unit of the reference hospital. The primary objective was to evaluate the correct diagnosis of RA or axial SpA cases confirmed by the rheumatologist of the reference hospital. RA-Substudy: A total of 340 patients were recruited (144 in ...
NO is present in the blood at 10(-7) M under physiological conditions, but at concentrations high... more NO is present in the blood at 10(-7) M under physiological conditions, but at concentrations higher than 10(-6) M during inflammatory disease states. The aim of this study was to characterize what are the effects of these different NO concentrations on erythrocyte structural and functional properties. Blood was collected from eleven healthy men and incubated with SpermineNONOate in order to expose it during incubation time to NO concentrations between 10(-7) M and 10(-3) M. We measured erythrocyte aggregation and deformability, membrane lipid peroxidation and fluidity, p50, hemoglobin, oxyhemoglobin, methemoglobin concentrations and plasma pH, pO(2), pCO(2), Na(+), K(+) and Ca(2+). When blood was exposed to NO 10(-7) M erythrocyte deformability increase and p50 decrease. In presence of NO 10(-5) M lipid fluidity and p50 decrease. When blood was exposed to NO 10(-3) M methemoglobin concentration increase and erythrocyte deformability and p50 decrease but membrane fluidity and lipid p...
Previous studies have documented structural and functional changes induced by ethanol-erythrocyte... more Previous studies have documented structural and functional changes induced by ethanol-erythrocyte membrane interaction. In order to perform an in vitro study on the effect of different ethanol concentrations on erythrocyte hemorheologic properties, blood samples were collected from 21 male donors at the Hospital of Santa Maria. Whole blood aliquots were incubated with ethanol solutions of rising concentrations. The following parameters were measured: erythrocyte aggregation, haemoglobin, carboxyhaemoglobin and methaemoglobin concentrations, hematocrit, plasma osmolality and erythrocyte membrane fluidity (fluorescence polarisation probes TMA-DPH and DPH). With ethanol blood concentrations of 45 mM a rise in plasma osmolality (0.352 Osm/kg H2O vs 0.310 Osm/kg H2O; p < 0.001) was verified. With 67 mM concentration a decrease of erythrocyte aggregation (11.03 vs 12.81; p < 0.05) and an increase in plasma osmolality (0.380 Osm/kg H2O vs 0.310 Osm/kg H2O; p < 0.001) were obtained...
To compare health care utilization between duloxetine initiators and pregabalin initiators among ... more To compare health care utilization between duloxetine initiators and pregabalin initiators among fibromyalgia patients in a real-world setting. METHODS: A retrospective cohort study was conducted based on a US national commercial health claims database (2006-2009). Fibromyalgia patients who initiated duloxetine or pregabalin in 2008, age 18 to 64, and maintained continuous health insurance coverage one year before and one year after initiation were as
The pathways which regulate resolution of inflammation and contribute to positive remodeling of t... more The pathways which regulate resolution of inflammation and contribute to positive remodeling of the myocardium following injury are poorly understood. Here we show that protein kinase C epsilon (PKC) cooperates with the phosphatase calcineurin (CN) to potentiate induction of cardioprotective gene expression while suppressing expression of fibrosis markers. This was achieved by detailed analysis of the regulation of cyclooxygenase 2 (COX-2) expression as a marker gene and by using gene expression profiling to identify genes regulated by coexpression of CN-A␣/PKC in adult rat cardiac myofibroblasts (ARVFs) on a larger scale. GeneChip analysis of CN-A␣/PKC-coexpressing ARVFs showed that COX-2 provides a signature for wound healing and is associated with downregulation of fibrosis markers, including connective tissue growth factor (CTGF), fibronectin, and collagens Col1a1, Col3a1, Col6a3, Col11a1, Col12a1, and Col14a1, with concomitant upregulation of cardioprotection markers, including COX-2 itself, lipocalin 2 (LCN2), tissue inhibitor of metalloproteinase 1 (TIMP-1), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). In primary rat cardiomyocyte cultures Toll-like receptor 4 (TLR4) agonist-or PKC/CNdependent COX-2 induction occurred in coresident fibroblasts and was blocked by selective inhibition of CN or PKC ␣/ or elimination of fibroblasts. Furthermore, ectopic expression of PKC and CN in ARVFs showed that the effects on COX-2 expression are mediated by specific NFAT sites within the COX-2 promoter as confirmed by site-directed mutagenesis and chromatin immunoprecipitation (ChIP). Therefore, PKC may negatively regulate adverse myocardial remodeling by cooperating with CN to downregulate fibrosis and induce transcription of cardioprotective wound healing genes, including COX-2.
Despite the widespread availability of biologics across Europe, rheumatoid arthritis (RA) patient... more Despite the widespread availability of biologics across Europe, rheumatoid arthritis (RA) patients&amp;amp;amp;amp;#39; access to these drugs differs significantly among countries. To compare the proportion of RA patients treated with biologics across Europe and investigate the factors that most influence it, with focus on the Portuguese case, reportedly with low access rates to biologics. The biologics&amp;amp;amp;amp;#39; market was characterized for 15 selected European countries. Variables potentially influencing patients&amp;amp;amp;amp;#39; access to biologics (PAB) in RA were also collected, including demographic, disease, economic, funding and biologics&amp;amp;amp;amp;#39; market-related data. A multivariable regression model identified the factors that best explain PAB. Based on these determinants, a cluster analysis was performed to group the countries with most similar behaviour regarding PAB allowing the evaluation of Portugal&amp;amp;amp;amp;#39;s relative position among these countries. The regression model (R(2) = 0.953) indicated that PAB in selected countries is explained mostly by its gross domestic product (GDP) per capita, the usage of methotrexate (MTX) and the biologics&amp;amp;amp;amp;#39; distribution channel. Current MTX usage in Portugal shows similarity with practice from UK, France, Germany or Spain 5 years before, explaining why PAB in Portugal stood at 7% in 2010, 12 percentage points below the average of selected countries. Variations in RA PAB were found across selected countries with Portugal showing the lowest proportion. GDP per capita, biologics distribution channel and consumption of MTX appear to be the best explanatory factors for these fluctuations in European countries.
Previous studies have documented structural and functional changes induced by ethanol-erythrocyte... more Previous studies have documented structural and functional changes induced by ethanol-erythrocyte membrane interaction. In order to perform an in vitro study on the effect of different ethanol concentrations on erythrocyte hemorheologic properties, blood samples were collected from 21 male donors at the Hospital of Santa Maria. Whole blood aliquots were incubated with ethanol solutions of rising concentrations. The following parameters were measured: erythrocyte aggregation, haemoglobin, carboxyhaemoglobin and methaemoglobin concentrations, hematocrit, plasma osmolality and erythrocyte membrane fluidity (fluorescence polarisation probes TMA-DPH and DPH). With ethanol blood concentrations of 45 mM a rise in plasma osmolality (0.352 Osm/kg H2O vs 0.310 Osm/kg H2O; p &amp;amp;lt; 0.001) was verified. With 67 mM concentration a decrease of erythrocyte aggregation (11.03 vs 12.81; p &amp;amp;lt; 0.05) and an increase in plasma osmolality (0.380 Osm/kg H2O vs 0.310 Osm/kg H2O; p &amp;amp;lt; 0.001) were obtained. In conclusion, ethanol only changes erythrocyte aggregation for a concentration of 67 mM. These data could lead to future changes in therapeutic approaches to situations such as alcoholic coma.
NO is present in the blood at 10 −7 M under physiological conditions, but at concentrations highe... more NO is present in the blood at 10 −7 M under physiological conditions, but at concentrations higher than 10 −6 M during inflammatory disease states. The aim of this study was to characterize what are the effects of these different NO concentrations on erythrocyte structural and functional properties. Blood was collected from eleven healthy men and incubated with SpermineNONOate in order to expose it during incubation time to NO concentrations between 10 −7 M and 10 −3 M. We measured erythrocyte aggregation and deformability, membrane lipid peroxidation and fluidity, p50, hemoglobin, oxyhemoglobin, methemoglobin concentrations and plasma pH, pO2, pCO2, Na + , K + and Ca 2+. When blood was exposed to NO 10 −7 M erythrocyte deformability increase and p50 decrease. In presence of NO 10 −5 M lipid fluidity and p50 decrease. When blood was exposed to NO 10 −3 M methemoglobin concentration increase and erythrocyte deformability and p50 decrease but membrane fluidity and lipid peroxidation were similar to control. In conclusion, dependent of NO concentrations there is different effects on erythrocytes structural and functional properties.
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Papers by Rui Mesquita