The therapeutic potential of dopamine modulators on the cardiovascular and renal systems

In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Gludopa is selective for the kidney thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.

The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET.) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ETA) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ETA receptor antagonism may have a role in the treatment of athero-sclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ETA receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the nonselective ET or selective ETA receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors tors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.

Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6

Tamoxifen is primarily used in the treatment of breast cancer. It has been approved as a chemopreventive agent for individuals at high risk for this disease. Tamoxifen is metabolized to a number of different products by cytochrome P450 enzymes. The effect of tamoxifen on the enzymatic activity of bacterially expressed human cytochrome CYP2B6 in a reconstituted system has been investigated. The 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation activity of purified CYP2B6 was inactivated by tamoxifen in a time- and concentration-dependent manner. Enzymatic activity was lost only in samples that were incubated with both tamoxifen and NADPH. The inactivation was characterized by a K-l of 0.9 muM, a k(inact) of 0.02 min(-1), and a t(1/2) of 34 min. The loss in the 7-ethoxy-4-(trifluoromethyl) coumarin O-deethylation activity did not result in a similar percentage loss in the reduced carbon monoxide spectrum, suggesting that the heme moiety was not the major site of modification. The activity of CYP2B6 was not recovered after removal of free tamoxifen using spin column gel filtration. The loss in activity seemed to be due to a modification of the CYP2B6 and not reductase because adding fresh reductase back to the inactivated samples did not restore enzymatic activity. A reconstituted system containing purified CYP2B6, NADPH-reductase, and NADPH-generating system was found to catalyze tamoxifen metabolism to 4-OH-tamoxifen, 4'-OH-tamoxifen, and N-desmethyl-tamoxifen as analyzed by high-performance liquid chromatography analysis. Preliminary studies showed that tamoxifen had no effect on the activities of CYP1B1 and CYP3A4, whereas CYP2D6 and CYP2C9 exhibited a 25% loss in enzymatic activity.

Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro

Purpose. The flux of a topically applied drug depends on the activity in the skin and the interaction between the vehicle and skin. Permeation of vehicle into the skin can alter the activity of drug and the properties of the skin barrier. The aim of this in vitro study was to separate and quantify these effects. Methods. The flux of four radiolabeled permeants (water, phenol, diflunisal, and diazepam) with log K-oct/water values from 1.4 to 4.3 was measured over 4 h through heat-separated human epidermis pretreated for 30 min with vehicles having Hildebrand solubility parameters from 7.9 to 23.4 (cal/cm(3))(1/2). Results. Enhancement was greatest after pretreatment with the more lipophilic vehicles. A synergistic enhancement was observed using binary mixtures. The flux of diazepam was not enhanced to the same extent as the other permeants, possibly because its partitioning into the epidermis is close to optimal (log K-oct 2.96). Conclusion. An analysis of the permeant remaining in the epidermis revealed that the enhancement can be the result of either increased partitioning of permeant into the epidermis or an increasing diffusivity of permeants through the epidermis.

On the discovery of business processes orchestration patterns

COORDINSPECTOR is a Software Tool aiming at extracting the coordination layer of a software system. Such a reverse engineering process provides a clear view of the actually invoked services as well as the logic behind such invocations. The analysis process is based on program slicing techniques and the generation of, System Dependence Graphs and Coordination Dependence Graphs. The tool analyzes Common Intermediate Language (CIL), the native language of the Microsoft .Net Framework, thus making suitable for processing systems developed in any .Net Framework compilable language. COORDINSPECTOR generates graphical representations of the coordination layer together with business process orchestrations specified in WSBPEL 2.0

International mobility in the Pharmacy degree at the school of allied health sciences of Oporto

Background: The Erasmus program is a subprogram of the Lifelong Learning program, exclusive for Higher Education that promotes (among other initiatives), the mobility of students(studies, training or internships). The mobility of students of higher education seeks to improve the quality and development of future professionals, providing a multidisciplinary and multicultural experience. Setting: Academic Pharmacy/Pharmacy Technicians Methods: We conducted a descriptive and transversal study on the implementation of the mobility program and analyze the results, which involved applying a survey to students. Results: Since 2009/2010, the Pharmacy Degree at ESTSP has established 7 SMs protocols resulting in an average mobility of 5 students IN and 7 Students OUT. We have also endeavoured in SMp Protocols for extracurricular training with an average of 3 students OUT. The application process is normally open during the year before the mobility period. For most of the students involved, this was a first time opportunity to be in a foreign country and more than 70% choose the mobility program because it is seen as a possibility to improve their curriculum, for personal development or even to pursue employment opportunities abroad. The mobility for teachers is also encouraged. Conclusions: The exchange of experiences and training, acquired during cooperation activities should be an element of continuous dynamics and institutional affirmation. Initiatives such as the ERASMUS Program contribute to the educational and scientific enrichment, and promote international competitiveness among Higher Education Institutions.

Direct medical costs associated with schizophrenia relapses in health care services in the city of São Paulo

OBJECTIVE: To assess direct medical costs associated with schizophrenia relapses in mental health services. METHODS: The study was conducted in three health facilities in the city of São Paulo: a public state hospital; a Brazilian National Health System (SUS)-contracted hospital; and a community mental health center. Medical records of 90 patients with schizophrenia who received care in 2006 were reviewed. Information on inpatient expenditures was collected and used for cost estimates. RESULTS: Mean direct medical cost of schizophrenia relapses per patient was US$ 4,083.50 (R$ 8,167.58) in the public state hospital; US$ 2,302.76 (R$ 4,605.46) in the community mental health center; and US$ 1,198.50 (R$ 2,397.74) in the SUS-affiliated hospital. The main component was daily inpatient room rates (87% - 98%). Medication costs varied depending on the use of typical or atypical antipsychotic drugs. Atypical antipsychotic drugs were more often used in the community mental health center. CONCLUSIONS: Costs associated with schizophrenia relapses support investments in antipsychotic drugs and strategies to reduce disease relapse and the need for mental health inpatient services. Treating patients in a community mental health center was associated with medium costs and added the benefit of not depriving these patients from family life.

Experiences on the implementation of a cooperative embedded system framework

As the complexity of embedded systems increases, multiple services have to compete for the limited resources of a single device. This situation is particularly critical for small embedded devices used in consumer electronics, telecommunication, industrial automation, or automotive systems. In fact, in order to satisfy a set of constraints related to weight, space, and energy consumption, these systems are typically built using microprocessors with lower processing power and limited resources. The CooperatES framework has recently been proposed to tackle these challenges, allowing resource constrained devices to collectively execute services with their neighbours in order to fulfil the complex Quality of Service (QoS) constraints imposed by users and applications. In order to demonstrate the framework's concepts, a prototype is being implemented in the Android platform. This paper discusses key challenges that must be addressed and possible directions to incorporate the desired real-time behaviour in Android.

Impact of long-stay beds on the performance of a tertiary hospital in emergencies

ABSTRACT OBJECTIVE To assess the impact of implementing long-stay beds for patients of low complexity and high dependency in small hospitals on the performance of an emergency referral tertiary hospital. METHODS For this longitudinal study, we identified hospitals in three municipalities of a regional department of health covered by tertiary care that supplied 10 long-stay beds each. Patients were transferred to hospitals in those municipalities based on a specific protocol. The outcome of transferred patients was obtained by daily monitoring. Confounding factors were adjusted by Cox logistic and semiparametric regression. RESULTS Between September 1, 2013 and September 30, 2014, 97 patients were transferred, 72.1% male, with a mean age of 60.5 years (SD = 1.9), for which 108 transfers were performed. Of these patients, 41.7% died, 33.3% were discharged, 15.7% returned to tertiary care, and only 9.3% tertiary remained hospitalized until the end of the analysis period. We estimated the Charlson comorbidity index – 0 (n = 28 [25.9%]), 1 (n = 31 [56.5%]) and ≥ 2 (n = 19 [17.5%]) – the only variable that increased the chance of death or return to the tertiary hospital (Odds Ratio = 2.4; 95%CI 1.3;4.4). The length of stay in long-stay beds was 4,253 patient days, which would represent 607 patients at the tertiary hospital, considering the average hospital stay of seven days. The tertiary hospital increased the number of patients treated in 50.0% for Intensive Care, 66.0% for Neurology and 9.3% in total. Patients stayed in long-stay beds mainly in the first 30 (50.0%) and 60 (75.0%) days. CONCLUSIONS Implementing long-stay beds increased the number of patients treated in tertiary care, both in general and in system bottleneck areas such as Neurology and Intensive Care. The Charlson index of comorbidity is associated with the chance of patient death or return to tertiary care, even when adjusted for possible confounding factors.

On the analysis of compensation correctness

One fundamental idea of service-oriented computing is that applications should be developed by composing already available services. Due to the long running nature of service interactions, a main challenge in service composition is ensuring correctness of transaction recovery. In this paper, we use a process calculus suitable for modelling long running transactions with a recovery mechanism based on compensations. Within this setting, we discuss and formally state correctness criteria for compensable processes compositions, assuming that each process is correct with respect to transaction recovery. Under our theory, we formally interpret self-healing compositions, that can detect and recover from faults, as correct compositions of compensable processes. Moreover, we develop an automated verification approach and we apply it to an illustrative case study.

Specifying a programming exercises evaluation service on the e-Framework

The e-Framework is arguably the most prominent e-learning framework currently in use. For this reason it was selected as basis for modelling a programming exercises evaluation service. The purpose of this type of evaluator is to mark and grade exercises in computer programming courses and in programming contests. By exposing its functions as services a programming exercise evaluator is able to participate in business processes integrating different system types, such as Programming Contest Management Systems, Learning Management Systems, Integrated Development Environments and Learning Object Repositories. This paper formalizes the approaches to be used in the implementation of a programming exercise evaluator as a service on the e-Framework.

A case study on the improvement of eco-efficiency ratios: application to a composite processing industry

The World Business Council for Sustainable Development (WBCSD) defines Eco-Efficiency as follows: ‘Eco- Efficiency is achieved by the delivery of competitively priced-goods and services that satisfy human needs and bring quality of life, while progressively reducing ecological impacts and resource intensity throughout the life-cycle to a level at least in line with the earth’s estimated carrying capacity’. Eco-Efficiency is under this point of view a key concept for sustainable development, bringing together economic and ecological progress. Measuring the Eco-Efficiency of a company, factory or business, is a complex process that involves the measurement and control of several and relevant parameters or indicators, globally applied to all companies in general, or specific according to the nature and specificities of the business itself. In this study, an attempt was made in order to measure and evaluate the eco-efficiency of a pultruded composite processing company. For this purpose the recommendations of WBCSD [1] and the directives of ISO 14301 standard [2] were followed and applied. The analysis was restricted to the main business branch of the company: the production and sale of standard GFRP pultrusion profiles. The main general indicators of eco-efficiency, as well as the specific indicators, were defined and determined according to ISO 14031 recommendations. With basis on indicators’ figures, the value profile, the environmental profile, and the pertinent eco-efficiency’s ratios were established and analyzed. In order to evaluate potential improvements on company eco-performance, new indicators values and ecoefficiency ratios were estimated taking into account the implementation of new proceedings and procedures, both in upstream and downstream of the production process, namely: a) Adoption of new heating system for pultrusion die in the manufacturing process, more effective and with minor heat losses; b) Implementation of new software for stock management (raw materials and final products) that minimize production failures and delivery delays to final consumer; c) Recycling approach, with partial waste reuse of scrap material derived from manufacturing, cutting and assembly processes of GFRP profiles. In particular, the last approach seems to significantly improve the eco-efficient performance of the company. Currently, by-products and wastes generated in the manufacturing process of GFRP profiles are landfilled, with supplementary added costs to this company traduced by transport of scrap, landfill taxes and required test analysis to waste materials. However, mechanical recycling of GFRP waste materials, with reduction to powdered and fibrous particulates, constitutes a recycling process that can be easily attained on heavy-duty cutting mills. The posterior reuse of obtained recyclates, either into a close-looping process, as filler replacement of resin matrix of GFRP profiles, or as reinforcement of other composite materials produced by the company, will drive to both costs reduction in raw materials and landfill process, and minimization of waste landfill. These features lead to significant improvements on the sequent assessed eco-efficiency ratios of the present case study, yielding to a more sustainable product and manufacturing process of pultruded GFRP profiles.

Influence of Immunopreventable Diseases and AIDS on the Demand of an Infectious Diseases Department in Rio de Janeiro State, Brazil, in the Course of Thirty Years (1965-1994)

Brazil's nosologic profile has been sustaining profound modifications. Some occurred because of massive immunization campaigns and socioeconomic and demographic trends. Some yet were pure nosologic transitions, such as the emergence of AIDS. In this demand study it is described how these changes reflected on the 8,630 admissions of an Infectious Diseases Department in Niterói, along a thirty year period. Brazilian rural endemic diseases were infrequent (3.45%). Men predominated (62%) all the time, in all age strata and in nearly all diseases. Children under fifteen predominated until 1983. There was, in the case of tetanus, a striking rise in age strata. Institutional mortality dropped from 31% in 1965 to 10% in 1984, but rose since then to 15% in 1994. However, if AIDS patients had not been computed, mortality would have kept descending till 8% at the end of the study period. The crescent unimportance of immunopreventable diseases paralleled with the growing prominence of AIDS. In less than a decade, AIDS ranked fifth among the most frequent diseases in the whole period of thirty years. As opposed to the immunopreventable diseases, neither meningitides nor pneumonia appear to be in decline. AIDS, by its exponential incidence, by its chronic character, and by the uncountable opportunistic infections it determines, imposes itself as a challenge for the coming years.

Parallelization of web processing services on cloud computing: A case study of Geostatistical Methods

Dissertation submitted in partial fulfillment of the requirements for the Degree of Master of Science in Geospatial Technologies.