A Doença Celíaca

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Farmacogenética/Farmacogenómica

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

A osteonecrose associada ao uso de bisfosfonatos

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina Dentária

Patient Retention in Antiretroviral Therapy Programs in Sub-Saharan Africa: A Systematic Review

Paper published in PLoS Medicine in 2007.

Rationing Antiretroviral Therapy for HIV/AIDS in Africa: Efficiency, Equity, and Reality

Background: Rationing of access to antiretroviral therapy already exists in sub-Saharan Africa and will intensify as national treatment programs develop. The number of people who are medically eligible for therapy will far exceed the human, infrastructural, and financial resources available, making rationing of public treatment services inevitable. Methods: We identified 15 criteria by which antiretroviral therapy could be rationed in African countries and analyzed the resulting rationing systems across 5 domains: clinical effectiveness, implementation feasibility, cost, economic efficiency, and social equity. Findings: Rationing can be explicit or implicit. Access to treatment can be explicitly targeted to priority subpopulations such as mothers of newborns, skilled workers, students, or poor people. Explicit conditions can also be set that cause differential access, such as residence in a designated geographic area, co-payment, access to testing, or a demonstrated commitment to adhere to therapy. Implicit rationing on the basis of first-come, first-served or queuing will arise when no explicit system is enforced; implicit systems almost always allow a high degree of queue-jumping by the elite. There is a direct tradeoff between economic efficiency and social equity. Interpretation: Rationing is inevitable in most countries for some period of time. Without deliberate social policy decisions, implicit rationing systems that are neither efficient nor equitable will prevail. Governments that make deliberate choices, and then explain and defend those choices to their constituencies, are more likely to achieve a socially desirable outcome from the large investments now being made than are those that allow queuing and queue-jumping to dominate.

How Much Does It Cost to Provide Antiretroviral Therapy for HIV/AIDS in Africa?

Background: Many African countries are rapidly expanding HIV/AIDS treatment programs. Empirical information on the cost of delivering antiretroviral therapy (ART) for HIV/AIDS is needed for program planning and budgeting. Methods: We searched published and gray sources for estimates of the cost of providing ART in service delivery (non-research) settings in sub-Saharan Africa. Estimates were included if they were based on primary local data for input prices. Results: 17 eligible cost estimates were found. Of these, 10 were from South Africa. The cost per patient per year ranged from $396 to $2,761. It averaged approximately $850/patient/year in countries outside South Africa and $1,700/patient/year in South Africa. The most recent estimates for South Africa averaged $1,200/patient/year. Specific cost items included in the average cost per patient per year varied, making comparison across studies problematic. All estimates included the cost of antiretroviral drugs and laboratory tests, but many excluded the cost of inpatient care, treatment of opportunistic infections, and/or clinic infrastructure. Antiretroviral drugs comprised an average of one third of the cost of treatment in South Africa and one half to three quarters of the cost in other countries. Conclusions: There is very little empirical information available about the cost of providing antiretroviral therapy in non-research settings in Africa. Methods for estimating costs are inconsistent, and many estimates combine data drawn from disparate sources. Cost analysis should become a routine part of operational research on the treatment rollout in Africa.

Non-clinical outcomes of antiretroviral therapy for HIV/AIDS in developing countries: a systematic literature review

The impacts of antiretroviral therapy on quality of life, mental health, labor productivity, and economic wellbeing for people living with HIV/AIDS in developing countries are only beginning to be measured. We conducted a systematic literature review to analyze the effect of antiretroviral therapy (ART) on these non-clinical indicators in developing countries and assess the state of research on these topics. Both qualitative and quantitative studies were included, as were peer-reviewed articles, gray literature, and conference abstracts and presentations. Findings are reported from 12 full-length articles, 7 abstracts, and 1 presentation (representing 16 studies). Compared to HIV-positive patients not yet on treatment, patients on ART reported significant improvements in physical, emotional and mental health and daily function. Work performance improved and absenteeism decreased, with the most dramatic changes occurring in the first three months of treatment and then leveling off. Little research has been done on the impact of ART on household wellbeing, with modest changes in child and family wellbeing within households where adults are receiving ART reported so far. Studies from developing countries have not yet assessed non-clinical outcomes of therapy beyond the first year; therefore, longitudinal outcomes are still unknown. As ART roll out extends throughout high HIV prevalence, low-resource countries and is sustained over years and decades, both positive and adverse non-clinical outcomes need to be empirically measured and qualitatively explored in order to support patient adherence and maximize treatment benefits.

Mainstream technology as an occupational therapy tool: technophobe or technogeek?

Occupational therapists need to embrace the use of mainstream technology in their quest to ensure that therapy remains current and meaningful to their clients. Technology can be useful to improve both functional independence and occupational performance. This opinion piece introduces how occupational therapists can apply mainstream technologies, including information and communication technologies such as the internet, computer software, portable devices and computer games, in their everyday interventions.

Investigation of the genetic susceptibility to osteoporosis in the Irish population

Osteoporosis is a complex skeletal disorder characterized by compromised bone strength. Variation in bone mineral density (BMD) is a contributing factor. The aim of this research as to select informative single nucleotide polymorphisms (SNPs) in potential candidate genes from loci suggestively linked to BMD variation for fine mapping. The gene regulated by oestrogen in breast cancer 1 (GREB1), located at 2p25.1, was selected. GREB1 transcription is initiated early in the oestrogen receptor alpha regulated pathway. There was significant association between GREB1_03 and BMD variation at the lumbar spine and femoral neck (FN) in the discovery cohort. Significant association was observed between GREB1_04 and FN BMD in the replication cohort. The development and differentiation enhancing factor 2, the integrin cytoplasmic domain associated protein 1 and A-disintegrin and metalloprotease 17 were selected due to their respective roles in cell mobility and adhesion. There was no linkage or association observed between the Chr2 cluster SNPs and BMD. Two factors in bone remodelling are the attraction of bone cell precursors and endocrine regulation of the process, primarily through the action of parathyroid hormone (PTH). The C-C chemokine receptor type 3 (CCR3) encodes a CC chemokine receptor expressed in osteoclast precursors. The PTH receptor type 1 (PTHR1) encodes a G-protein coupled receptor for PTH. Association was observed between CCR3 haplotypes and BMD variation at the FN. There was no linkage or association observed between PTHR1 SNPs and BMD variation. Population genetic studies with complex phenotypes endeavour to elucidate the traits genetic architecture. This study presents evidence of association between GREB1 and BMD variation and as such, introduces GREB1 as a novel gene target for osteoporosis genetics studies. It affirms that common genomic variants in PTHR1 are not associated with BMD variation in Caucasians and supports the evidence that CCR3 may be contributing to BMD variation

A study of diet and health in the elderly; the gut microbiota as a source of bioactive agents

The global proportion of older persons is increasing rapidly. Diet and the intestinal microbiota independently and jointly contribute to health in the elderly. The habitual dietary patterns and functional microbiota components of elderly subjects were investigated in order to identify specific effector mechanisms. A study of the dietary intake of Irish community-dwelling elderly subjects showed that the consumption of foods high in fat and/or sugar was excessive, while consumption of dairy foods was inadequate. Elderly females typically had a more nutrient- dense diet than males and a considerable proportion of subjects, particularly males, had inadequate intakes of calcium, magnesium, vitamin D, folate, zinc and vitamin C. The association between dietary patterns, glycaemic index and cognitive function was also investigated. Elderly subjects consuming ‘prudent’ dietary patterns had better cognitive function compared to those consuming ‘Western’ dietary patterns. Furthermore, fully-adjusted regression models revealed that a high glycaemic diet was associated with poor cognitive function, demonstrating a new link between nutrition and cognition. An extensive screening study of the elderly faecal-derived microbiota was also undertaken to examine the prevalence of antimicrobial production by intestinal bacteria. A number of previously characterised bacteriocins were isolated (gassericin T, ABP-118, mutacin II, enterocin L-50 and enterocin P) in this study. Interestingly, a Lactobacillus crispatus strain was found to produce a potentially novel antimicrobial compound. Full genome sequencing of this strain revealed the presence of three loci which exhibited varying degrees of homology with the genes responsible for helveticin J production in Lb. helveticus. An additional study comparing the immunomodulatory capacity of ‘viable’ and ‘non-viable’ Bifidobacterium strains found that Bifidobacterium-fermented milks (BFMs) containing ‘non-viable’ cells could stimulate levels of IL-10 and TNF-α in a manner similar to those stimulated by BFMs containing ‘viable’ cells in vitro.

Mesenchymal stem cell therapy for the treatment of myocardial infarction

Mesenchymal stem cells (MSCs) are currently under investigation as repair agents in the preservation of cardiac function following myocardial infarction (MI). However concerns have emerged regarding the safety of acute intracoronary (IC) MSC delivery specifically related to mortality, micro-infarction and microvascular flow restriction post cell therapy in animal models. This thesis aimed to firstly identify an optimal dose of MSC that could be tolerated when delivered via the coronary artery in a porcine model of acute MI (AMI). Initial dosing studies identified 25x106 MSC to be a safe MSC cell dose, however, angiographic observations from these studies recognised that on delivery of MSC there was a significant adverse decrease in distal blood flow within the artery. This observation along with additional supportive data in the literature (published during the course of this thesis) suggested MSC may be contributing to such adverse events through the propagation of thrombosis. Therefore further studies aimed to investigate the innate prothrombotic activity of MSC. Expression of the initiator of the coagulation cascade initiator tissue factor (TF) on MSC was detected in high levels on the surface of these cells. MSC-derived TF antigen was catalytically active, capable of supporting thrombin generation in vitro and enhancing platelet-driven thrombus deposition on collagen under flow. Infusion of MSC via IC route was associated with a decreased coronary flow reserve when delivered but not when coadministered with an antithrombin agent heparin. Heparin also reduced MSC-associated in situ thrombosis incorporating platelets and VWF in the microvasculature. Heparin-assisted MSC delivery reduced acute apoptosis and significantly improved infarct size, left ventricular ejection fraction, LV volumes, wall motion and scar formation at 6 weeks post AMI. In addition, this thesis investigated the paracrine factors secreted by MSC, in particular focusing on the effect on cardiac repair of a novel MSC-paracrine factor SPARCL1. In summary this work provides new insight into the mechanism by which MSC may be deleterious when delivered by an IC route and a means of abrogating this effect. Moreover we present new data on the MSC secretome with elucidation of the challenges encountered using a single paracrine factor cardiac repair strategy.

Effectiveness of rescue antiretroviral therapy including intravenously administered zidovudine and foscarnet in a child with HIV-1 enteropathy.

Case Reports

Adjuvant therapy in elderly patients with breast cancer.

The elderly population has been neglected by the traditional approach to clinical breast cancer research. Elderly women have been underrepresented in breast cancer clinical trials, with the majority of studies being restricted to patients aged < 70 years. Elderly patients frequently have comorbidities and/or impaired organ function. These facts may often lead to death from causes other than cancer, thus nullifying any possible benefit of adjuvant treatment; furthermore, they render extrapolation of standard treatment recommendations to the elderly potentially hazardous, particularly with respect to chemotherapy. Therefore, specific clinical trials are needed to investigate adjuvant treatments tailored for the heterogeneous older population.

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer.

BACKGROUND: Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. PATIENTS AND METHODS: Patients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. RESULTS: Blinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. CONCLUSIONS: Exemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.

A feasibility study evaluating docetaxel-based sequential and combination regimens in the adjuvant therapy of node-positive breast cancer

BACKGROUND AND PURPOSE: Docetaxel is an active agent in the treatment of metastatic breast cancer. We evaluated the feasibility of docetaxel-based sequential and combination regimens as adjuvant therapies for patients with node-positive breast cancer. PATIENTS AND METHODS: Three consecutive groups of patients with node-positive breast cancer or locally-advanced disease, aged < or = 70 years, received one of the following regimens: a) sequential A-->T-->CMF: doxorubicin 75 mg/m2 q 3 weeks x 3, followed by docetaxel 100 mg/m2 q 3 weeks x 3, followed by i.v. CMF days 1 + 8 q 4 weeks x 3; b) sequential accelerated A-->T-->CMF: A and T were administered at the same doses q 2 weeks; c) combination therapy: doxorubicin 50 mg/m2 + docetaxel 75 mg/m2 q 3 weeks x 4, followed by CMF x 4. When indicated, radiotherapy was administered during or after CMF, and tamoxifen started after the end of CMF. RESULTS: Seventy-nine patients have been treated. Median age was 48 years. A 30% rate of early treatment discontinuation was observed in patients receiving the sequential accelerated therapy (23% during A-->T), due principally to severe skin toxicity. Median relative dose-intensity was 100% in the three treatment arms. The incidence of G3-G4 major toxicities by treated patients, was as follows: skin toxicity a: 5%; b: 27%; c: 0%; stomatitis a: 20%; b: 20%; c: 3%. The incidence of neutropenic fever was a: 30%; b: 13%; c: 48%. After a median follow-up of 18 months, no late toxicity has been reported. CONCLUSIONS: The accelerated sequential A-->T-->CMF treatment is not feasible due to an excess of skin toxicity. The sequential non accelerated and the combination regimens are feasible and under evaluation in a phase III trial of adjuvant therapy.