Plano de marketing Iatros Clinic 2012-2013

Mestrado em MarketingPor todo o mundo assiste-se ao envelhecimento da população, e Portugal não é excepção. Conta neste momento com 1,9 milhões de idosos residentes no país que necessitam de cuidados especializados para as suas necessidades. Com o intuito de prestar este serviço, este trabalho apresenta um Plano de Marketing para o lançamento de uma clínica especializada em geriatria. O plano descreve as envolventes externas e internas da clínica, incluindo uma análise da concorrência e dos seus possíveis factores-chave de sucesso. Descreve também a segmentação, mercado-alvo e posicionamento, e ainda os objectivos de marketing e financeiros que se pretendem atingir nos dois primeiros anos de funcionamento. O marketing-mix encontra-se dividido em sete pontos: Serviço, Preço, Distribuição, Comunicação, Pessoas, Processo e Evidências Físicas. O ponto chave deste plano são os recursos humanos, pois são eles que irão prestar os serviços disponibilizados pela clínica, mas que também irão contribuir para a possibilidade de adequar os preços praticados ao poder económico do público-alvoAll over the world, the population is getting older, and Portugal is not an exception. Nowadays, there are 1.9 million inhabitants older than 65 years old that need specialized health care. In order to satisfy this need, this work presents a Marketing Plan for the creation of a clinic specialized in geriatrics. The plan describes the clinic's external and internal environment, including a competition analysis and key-factors for success. It also describes segmentation, targeting and positioning, and even marketing and financial objectives for the first two years of the clinic. In the marketing-mix there are seven topics: Service, Price, Placement, Promotion, People, Process and Physical Evidence. The key-point of this plan is human resources. They are the ones that will provide the clinic services available to patients and also, the ones that will allow to adapt the prices to the current economic situation of the target population

Alertas de segurança : impacto no consumo de medicamentos em Portugal

Mestrado em Biomedicina FarmacêuticaEste estudo teve como objetivos a recolha e análise dos alertas de segurança a medicamentos publicados em Portugal, bem como avaliar o impacto dos alertas de segurança para medicamentos contendo rosiglitazona como substância ativa nas vendas de antidiabéticos em Portugal. Foi conduzida uma pesquisa dos alertas de segurança publicados pelo INFARMED, I.P. e pela EMA, complementada pela análise dos alertas publicados nos Boletins de Farmacovigilância. Para o estudo do impacto dos alertas da rosiglitazona desenhou-se um modelo de análise de regressão segmentada, usada para avaliar as diferenças ocorridas após cada um dos quatro alertas de segurança relacionados com a substância ativa rosiglitazona. Observou-se que dos 106 alertas selecionados, 43 são mencionados nos Boletins de Farmacovigilância. Entre 2000 e 2012, manteve-se a tendência do tipo de medida de segurança mais frequente, com o maior número de alertas relacionado com a alteração do Resumo das Características do Medicamento e Folheto Informativo e 17 alertas levaram à retirada do medicamento do mercado, temporária ou definitivamente, de forma voluntária ou não. O impacto dos alertas de segurança a medicamentos contendo rosiglitazona como substância ativa, foi de aumento de 32,9% (0,202 DID, p 0,05) e 0,24% (-0,001 DID, p> 0,05), respetivamente. É importante para os profissionais de saúde e para os doentes terem acesso rápido e claro à informação de segurança relacionada com os medicamentos. A avaliação dos alertas de segurança é importante para aceder à relação benefício-risco de um medicamento e melhorar a sua utilização pela população.This study aimed the collection and analysis of safety alerts published in Portugal, as well as assessing the impact of rosiglitazone safety alerts in the sales of oral antidiabetics in Portugal. We conducted a search of safety alerts published by INFARMED, I.P. and EMA, and complemented with analysis of Pharmacovigilance Bulletins. To study the impact of the warnings of rosiglitazone it was drawn up a model of segmented regression analysis, used to assess differences occurred after each of the four safety alerts related to rosiglitazone. It was observed that from the 106 selected alerts, 43 are mentioned in Pharmacovigilance Bulletins. Between 2000 and 2012, the trend remained with the change in the SPC and PL as the most frequent safety measure taken and 17 safety alerts leading to withdrawal, either temporarily or permanently, voluntarily or not. The impact of rosiglitazone safety alert, was an increase of 32.9 % (0.202 DID, p0.05) and 0.24 % (DID -0.001, p>0.05), respectively. It was observed that safety alerts conditioned the life cycle of rosiglitazone and the effects of safety alerts are immediately felt in the sales of other oral antidiabetic agents. It is important for healthcare professionals and patients have a quick and clear safety information related to drugs. The evaluation of safety alerts is important to access the benefit-risk ratio of a drug and to improve the use of medication, improving patient safety

Oxidative stress function in women over 40 years of age, considering their lifestyle

Aging is dependent on biological processes that determine the aging of the organism at the cellular level. The Oxidative Stress Theory of Aging might explain some of the age-related changes in cell macromolecules. Moreover, exposome and lifestyle may also induce changes in cell damage induced by oxidative stress. The aim of the present study was to analyze the related redox changes in lymphocyte function of healthy women over 40 years old. Three groups: younger (YG: 40–49 years), middle aged (MAG: 50–59 years), and older (OG: ≥60 years) were evaluated on anthropometric variables, blood pressure, cardiovascular fitness, lifestyle habits, perceived stress, DNA damage, malondialdehyde, catalase activity, and total antioxidant capacity. Physical activity and cardiovascular fitness were significantly higher in YG and MAG as compared to the OG. Systolic blood pressure increased significantly with group age. Frequency and total amount of alcohol intake were lower in the OG and higher in the MAG. No significant differences were observed between the three groups in oxidative stress parameters. Only alcohol consumption was associated with the higher DNA FPG-sensitive sites, and only in the YG (p < 0.05). Healthy lifestyle is critical to avoiding major ailments associated with aging. This may be inferred from the lack of significant differences in the various oxidative stress parameters measured in the healthy women over the age of 40 who took part in the study. Conscious lifestyle behaviors (decrease in alcohol and smoking habits) could have impaired the expected age-related oxidative stress increase.info:eu-repo/semantics/publishedVersio

Stroke in children with sickle cell disease: advances in understanding its molecular pathogenesis

Sickle Cell Disease (SCD) is a clinically heterogeneous monogenic chronic anaemia characterized by severe recurrent episodes of vaso-occlusion, infection, and chronic haemolysis. Cerebral vasculopathy (overt stroke and silent infarcts) is one of the most devastating complications affecting these children. However, its pathophysiology is complex and the underlying mechanisms remain largely unknown. The main objective of this study was to search for associations between putative genetic modifiers of vascular tonus, vascular cell adhesion and inflammation, and the risk for cerebral infarcts, particularly overt stroke, in the context of SCD in paediatric patients. Sixty six children with SCD were enrolled in this work. They were divided into three groups, according to different inclusion criteria: Stroke group (n=13), included children with at least one episode of stroke between ages 5 and 13; Risk group (n=29) included children with high transcranial Doppler (TCD) velocities and children with silent infarcts on magnetic resonance imaging (MRI); and Control group (n= 24) included children without previous history of stroke, normal TCD velocities and no abnormalities on MRI. Clinical, biochemical, haematological and imaging data were retrospectively obtained from patients’ medical records. Several molecular biology methodologies (such as, PCR-RFLP, Gap-PCR, Sequencing, and Gene Scan) were used to characterize 23 genetic variants of 12 candidate genes. Statistical analysis was performed using R software. Six SNPs in genes (VCAM-1, THBS-1, HMOX, and NOS3), and four haplotypes (in the promoters of VCAM-1 and NOS3) were found to be associated with some of the studied phenotypes. However, only two SNPs and one haplotype maintained significance after FDR correction of p-values, with 90% confidence. The (-2021)T variant in the promoter of VCAM-1 (rs1409419) and the (-786)C variant in NOS3 (rs2070744) were positively associated with Stroke, whereas Haplotype 5 in NOS3 was positively associated with Control group, all for allele count and dominant mode of transmission. These gene variants seem to modulate the cerebral vasculopathy due to their capacity to quantitatively modify gene expression and, consequently, their corresponding protein products biological activities. Additionally, it was observed that patients who presented high HbF levels (>10%) were less prone to stroke ischemic events. Moreover, Risk group showed a positive association with higher LDH levels when compared to the other groups, suggesting that higher degree of haemolysis is a risk factor for stroke

Stroke risk in children with sickle cell anemia – the importance of genetic modulators of hemolysis

Sickle cell anemia (SCA) is an autosomal recessive disease, caused by the mutation HBB:c.20A>T, originating hemoglobin (Hb) S that, upon deoxygenation, polymerises inside the erythrocyte, deforming it and leading to premature hemolysis. The disease presents high clinical heterogeneity, stroke being the most devastating manifestation. It occurs in 11% of patients by 20 years of age. In this study we aimed to identify genetic modulators of stroke risk in SCA. Sixty six children with SCA were categorised according to their degree of cerebral vasculopathy: Stroke (n=13), Risk (n=29) and Control (n= 24). Relevant data were collected from patients’ medical records. We characterized 23 polymorphic regions in genes related to vascular cell adhesion (VCAM-1, THBS-1, CD36), vascular tonus (NOS3, ET-1), and inflammation (TNF-α, HMOX-1) as well as in known globin expression modulators (HBB cluster haplotype; HBA and BCL11A genotypes). Data analyses were performed using R software. VCAM-1 rs1409419 allele C and NOS3 rs207044 allele C were associated to stroke events, while VCAM-1 rs1409419 allele T was found to be protective. Allele 4a of NOS3 27 bp VNTR appeared to be associated to stroke risk and the 4b allele to protection. HMOX-1 longer STRs seemed to predispose to stroke. Higher HbF levels (associated to Senegal haplotype or BCL11A rs11886868 allele T) were found in Control group, and higher lactate dehydrogenase levels were found in Risk group. The genetic variants above modulate cerebral vasculopathy development due to their quantitative effect on gene expression, their corresponding protein products and biological activities. Our findings reinforce the relevance of vascular tonus, vascular cell adhesion, and ultimately NO bioavailability and hemolysis rate in modulating SCA stroke development and provide the first evidence of a protective role of HbF against stroke occurrence

Influence of hormonal replacement therapy in lipid peroxidation levels of postmenopausal women with different cardiovascular capacity

It has been suggested that exercise has a positive impact on the prevention and progression of cardiovascular disease (CVD). One of the main mechanisms is through the modification of lipoprotein levels and the risk of its oxidation, especially LDL lipoproteins. After menopause, women experience an increased incidence of cardiovascular disease. In contrast, women receiving hormonal replacement therapy (HRT) seem to be protected. The aim of this study was to infer how HRT affect lipid peroxidation levels in postmenopausal women with different levels of aerobic fitness. Design & Method: Sixty four women participate in this study, 32 of them receive HRT (group with HRT – GWHRT) (average age¼55.9 years, average weight¼ 66.9 kg and average high¼156.0 cm) and the remained 32 women didn’t receive HRT (group without HRT – GWOHRT) (average age¼61.0 years, average weight¼ 67.6 kg and average high¼154.3 cm). Total cholesterol (mg dL71), HDL-cholesterol (mg dL71), LDL-cholesterol (mg dL71) and triglycerides levels (mg dL71) have been analyzed in serum obtained from a blood sample collected after 8 hours of fasting, and measured in Dr. Lange LP20 according to the specific manufacturer instructions. Serum MDA concentration (ng L71) was determined by spectrophotometric method. Aerobic capacity (VO2max ml kg71 min71) was assessed according to an adaptation of Bruce protocol. Differences between groups were tested through Student t-test. A Spearman correlation was performed in order to test variables associations. Significance level was established at 5%.Results: Our results have found differences between groups in age (t¼3.018; p50.01), in VO2max (t¼73.774; p50.01) and in serum MDA concentration (t¼6.750; p50.01). The GWHRT were younger, had a higher VO2max (31.38 for GWHRT and 26.19 for GWOHRT), and had lower levels of serum MDA concentration (0.29 for GWHRT and 0.73 for GWOHRT) comparatively with those women from the GWOHRT. However, our results failed to find any differences between groups regarding serum triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol or BMI. In this study, serum MDA concentration didn’t correlate with higher levels of lipid profile, as we might have expected, but correlate inversely with HRT (r¼7.726, p¼.00) and with VO2max (r¼7.287, p¼.02). Conclusion: Our results suggest that HRT should exert an antioxidant protective effect against lipid peroxidation, as well as exercise perhaps through the stimulation of antioxidant capacity

Effects of physical exercise training in DNA damage and repair - could the difference be in hOGG1 Ser326Cys polymorphism?

Acute physical exercise is associated with increased oxygen consumption, which could result in an increased formation of reactive oxygen species (ROS). ROS can react with several organic structures, namely DNA, causing strand breaks and a variety of modified bases in DNA. Physical exercise training seems to decrease the incidence of oxidative stress-associated diseases, and is considered as a key component of a healthy lifestyle. This is a result of exercise-induced adaptation, which has been associated with the possible increase in antioxidant activity and in oxidative damage repair enzymes, leading to an improved physiological function and enhanced resistance to oxidative stress (Radak et al. 2008). Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is involved in the base excision repair (BER) pathway and encodes an enzyme responsible for removing the most common product of oxidative damage in DNA, 8-hydroxyguanine (8-OH-G). The genetic polymorphism of hOGG1 at codon 326 results in a serine (Ser) to cysteine (Cys) amino acid substitution (Ser326Cys). It has been suggested that the carriers of at least one hOGG1Cys variant allele exhibit lower 8-OH-G excision activity than the wild-type (Wilson et al. 2011). The aim of this study was to investigate the possible influence of hOGG1 Ser326Cys polymorphism on DNA damage and repair activity in response to 16 weeks of combined physical exercise training, in thirty healthy Caucasian men. Comet assay was carried out using peripheral blood lymphocytes and enabled the evaluation of DNA damage, both strand breaks and FPG-sensitive sites, and DNA repair activity. Genotypes were determined by PCR-RFLP analysis. The subjects with Ser/Ser genotype were considered as wild-type group (n=20), Ser/Cys and Cys/Cys genotype were analyzed together as mutant group (n=10). Regarding differences between pre and post-training in the wild-type group, the results showed a significant decrease in DNA strand breaks (DNA SBs) (p=0.002) and also in FPG-sensitive sites (p=0.017). No significant differences were observed in weight (p=0.389) and in lipid peroxidation (MDA) (p=0.102). A significant increase in total antioxidant capacity (evaluated by ABTS) was observed (p=0.010). Regarding mutant group, the results showed a significant decrease in DNA SBs (p=0.008) and in weight (p=0.028). No significant differences were observed in FPG-sensitive sites (p=0.916), in ABTS (p=0.074) and in MDA (p=0.086). No significant changes in DNA repair activity were observed in both genotype groups. This preliminary study suggests the possibility of different responses in DNA damage to physical exercise training, considering the hOGG1 Ser326Cys polymorphism.This work was supported by Foundation of Science and Technology (FCT) for the research grant SFRH/BD/66438/2009 to JS and for the project entitled "Physical exercise role on Human’ lymphocyte DNA damage reduction: possible influence of oxidative stress and DNA repair capacity" PTDC/DES/121575/2010. We also would like to acknowledge FCT under the project UID/AGR/04033/2013

Genetic Modulation of Cerebral Vasculopathy in Children with Sickle Cell Anemia

Palestras de difusão da cultura científica dirigidas aos colaboradores internos do INSA, podendo incluir participantes externos envolvidos nos estudos e colegas de investigação da área de trabalho em questão.Sickle cell anemia (SCA) arises from homozygosity for the mutation c.20A>T in the HBB gene which originates hemoglobin S (HbS). In hypoxic conditions, HbS polymerizes inside erythrocytes deforming them and ultimately leading to hemolysis and vaso-occlusion. SCA shows a multifactorial-like behaviour with a high heterogeneity of clinical features, with stroke being the most severe of them. This heterogeneity may arise from underlying genetic modifiers, namely those affecting vascular hemostasis. These include genes like the ones encoding VCAM-1 and its ligand integrin α4 (expressed in activated human endothelium and leucocytes/stress reticulocytes, respectively), but also eNOS (expressed in human endothelium and regulating vascular tone). The aim of this study was to identify putative genetic modulators of stroke risk by analyzing 70 pediatric SCA patients, grouped according to their degree of cerebral vasculopathy. Molecular analysis was performed using Next-Generation Sequencing (NGS) and Sanger Sequencing. R software was used for statistical analyses and association studies. In silico studies were performed using PHASE, TFbind, PROMO and Human Splicing Finder software tools. We identified six different VCAM1 promoter variants and seven haplotypes. The VCAM1 promoter rs1409419_T allele was associated with stroke events, while one VCAM1 promoter haplotype was found to be protective of stroke. In the ITGA4 gene, forty variants were found, six of them novel. All patients presented with at least one variant in this gene. We observed co-inheritance of specific sets of ITGA4 variants indicating the presence of haplotypes not previously described. Three NOS3 variants were analysed and seven haplotypes were identified. The NOS3 promoter rs2070744_C allele was associated with stroke events, while the intron 4 VNTR 27bp_4a allele was found to be in association with risk of stroke. Our results reinforce the role of endothelial molecules and blood cell interaction in SCA severity. The association between specific variants in VCAM1 and ITGA4, as well as in NOS3, with certain cerebral vasculopathy predictors further enhances their putative modulating effect on pediatric stroke severity and prognosis. These findings provide additional clues on the SCA pathophysiology and uncover features of both genes that may prove to be crucial as potential therapeutic targets.N/

Paediatric cerebral vasculopathy in sickle cell anaemia: contribution of genetic modifiers

Sickle cell anaemia (SCA) arises from homozygosity for the mutation c.20A>T in the HBB gene. However, it shows a multifactorial-like behaviour with high heterogeneity of clinical features. Cerebral vasculopathy (CVA), namely paediatric ischemic stroke, is one of its most devastating consequences. The risk of CVA development, specifically stroke or silent cerebral infarction, may be modulated by underlying genetic modifiers, for example those affecting vascular homeostasis. In this study, we aimed to investigate the impact of variants in genes related with endothelial adhesion (VCAM1 and ITGA4) and nitric oxide metabolism (NOS3) on CVA in a group of 70 SCA children well characterized according to their CVA degree. In addition, the effect of the same genetic variants on biochemical/haematological biomarkers of chronic haemolysis was also analysed. Moreover, we also evaluated the putative additional modulating role of variants previously identified as stroke risk factors by genome-wide associated studies: GOLGB1 Y1212C, ENPP1 K173Q and PON1 Q192R. Molecular analysis was performed using PCR, PCR-RFLP, next-generation sequencing and Sanger sequencing. SPSS software was used for statistical analyses and association studies. One of the seven VCAM1 promoter haplotypes found and the VCAM1 promoter rs1409419_T showed association with moderate to high time-averaged mean of maximum velocity in the middle cerebral artery. The same association was observed for the variant ENPP1 K173Q. On the other hand, we observed that ITGA4 variants rs113276800_A and rs3770138_T were associated with stroke events. As for NOS3, one of the six haplotypes and the intron 4 VNTR_4b allele (5 repeats) were associated with lower risk of silent cerebral infarction. Chronic haemolysis biomarker levels also seemed to be influenced by genetic variants. LDH levels was higher in the presence of VCAM1 promoter rs1409419_T and one VCAM1 haplotype but lower in patients with one of the two ITGA4 haplotypes found. Genetic modulation also occurred in total bilirubin levels, which were higher in association with VCAM1 rs3783613_C allele. Our results, namely the association between specific variants with certain cerebral vasculopathy predictors further enhances their putative modulating effect on SCA paediatric stroke risk, severity and prognosis. These findings provide additional clues on the SCA pathophysiology and uncover features in these genes that may prove to be crucial as potential therapeutic targets.INSA_202DGH720 and ISAMBinfo:eu-repo/semantics/publishedVersio

Genetic modulation of stroke in children with sickle cell anaemia

Sickle cell anaemia (SCA) is an autosomal recessive genetic disease that leads to the synthesis of haemoglobin S (HbS). The pathophysiology of the disease is centred on HbS polymerization inside the red blood cells, which become sickle-shaped (SSRBCs), rigid, viscous and adherent-prone to the vascular endothelium, favouring the occurrence of chronic haemolysis and vaso-occlusion. The main vascular problems of SCA arise from several pathways including endothelial dysfunction and nitric oxide (NO) metabolism. Children with SCA have a much higher risk (11% by age 20 years) of developing stroke or silent cerebral infarcts (up to 37%) than the general paediatric population. Abnormal interactions between SSRBCs and the cerebral arterial endothelium lead to endothelial injury, vaso-occlusion and tissue ischemia and result in cerebral vasculopathy (CVA) through a yet unknown pathophysiological mechanism. Current risk screening strategies rely mainly on imaging techniques (transcranial Doppler ultrasonography and magnetic resonance imaging) and children with altered results undergo regular blood transfusion and/or hydroxyurea therapy to reduce stroke risk/recurrence. However, we need more specific/sensitive biomarkers for stroke prediction/prognosis. Genetic modulators may be paramount in SCA pathophysiology and in CVA severity. They include variants in VCAM1 (endothelial dysfunction), ITGA4 (cell-cell adhesion), and NOS3 (nitric oxide metabolism. The main goals of this work are: a) improve the knowledge on the genetic architecture of paediatric cerebral vasculopathy in SCA; b) assessing the consequences of those genetic variants on gene expression/protein function; c) identify genotypic/phenotypic markers of SCA sub-phenotypes; and d) analyse their potential as genetic modulators of disease severity. This would be crucial in assessing potential pharmacological targets specifically aimed to the vascular system and instrumental for the design of novel preventive, prophylactic or therapeutic strategies.INSA_202DGH72 and ISAMBN/