Chemical functionalization in bionanoparticles

Dissertação de mestrado em Biofísica e Bionanossistemas

Prescription and adherence to statins of patients with coronary artery disease and hypercholesterolemia

OBJECTIVE: Statins have proved to be safe and effective in the secondary prevention of coronary artery disease, but the level of prescription and the reasons for nonadherence to treatment in many coronariopathy treatment centers has not been determined. The purpose of this study was to identify reasons for nonadherence to statin therapy. METHODS: We analyzed 207 consecutive patients with coronary artery disease and hypercholesterolemia (total cholesterol > or = 200mg/dL or LDL - cholesterol > or = 130mg/dL). Patients' average age was 61.7±10 year; 111 (53.6%) male were and 94 (46.6%) were female. We analyzed the level of prescription and adherence to treatment with statins. RESULTS: Statins were prescribed for 139 (67%) patients, but only 85 (41%) used the drug. In spite of being indicated, statins were not prescribed in 68 (33%) patients. Of 54 (26%) patients, nonadherent to statins, 67% did not use the drug due to its high cost, 31% due to the lack of instruction, and only 2% due to side effects. Total cholesterol (260.3±42.2 vs 226.4±51.9; p<0.0001) and LDL cholesterol (174.6±38.1 vs 149.6±36.1; p<0.0001) were lower in patients on medication. HDL-cholesterol increased from 37.6±9.6 to 41.5±12.9mg/dL (p=0.02), and triglycerides were not modified in patients using statins. CONCLUSION: The prescription of statins in patients with coronary artery disease and dyslipidemia is high; however, its adherence is far from satisfactory, due to the high cost of the medication. Reduction in total cholesterol and LDL cholesterol levels did not reach the targets recommended by the Brazilian Consensus on Dyslipidemia.

Exercise stress testing in healthy subjects during cholinergic stimulation after a single dose of pyridostigmine

OBJETIVE: The evaluation, by exercise stress testing, of the cardiorespiratory effects of pyridostigmine (PYR), a reversible acetylcholinesterase inhibitor. METHODS: A double-blind, randomized, cross-over, placebo-controlled comparison of hemodynamic and ventilation variables of 10 healthy subjects who underwent three exercise stress tests (the first for adaptation and determination of tolerance to exercise, the other two after administration of placebo or 45mg of PYR). RESULTS: Heart rate at rest was: 68±3 vs 68±3bpm before and after placebo, respectively (P=0.38); 70±2 vs 59±2bpm, before and after pyridostigmine, respectively (P<0.01). During exercise, relative to placebo: a significantly lower heart rate after PYR at, respectively, 20% (P=0.02), 40% (P=0.03), 80% (P=0.05) and 100% (P=0.02) of peak effort was observed. No significant differences were observed in arterial blood pressure, oxygen consumption at submaximal and maximal effort, exercise duration, respiratory ratio, CO2 production, ventilation threshold, minute ventilation, and oxygen pulse. CONCLUSION: Pyridostigmine, at a dose of 45mg, decreases heart rate at rest and during exercise, with minimal side effects and without interfering with exercise tolerance and ventilation variables.

Anti-inflammatory and antinociceptive activities of Bauhinia monandra leaf lectin

A galactose-specific lectin from Bauhinia monandra leaves (BmoLL) have been purified through ammonium sulphate fractionation followed by guar gel affinity chromatography column. This study aimed to evaluate the potential anti-inflammatory and antinociceptive activity of pure BmoLL in mice. Anti-inflammatory activity was evaluated by 1% carrageenan-induced inflammation in mice treated with BmoLL. Acetic acid-induced abdominal writhing and hot plate methods evaluated antinociceptive activity. BmoLL significantly inhibited the carrageenan-induced paw edema by 47% (30 mg/kg) and 60.5% (60 mg/kg); acetylsalicylic acid (ASA, 100 mg/kg) showed inhibition of 70.5%, in comparison to controls. Leukocyte migration, an immune response to the inflammation process, was significantly reduced in presence of BmoLL; in mice treated with \ASA\ the decrease in leukocyte migration was similar to 15 mg/kg of the lectin. BmoLL at doses of 15, 30 and 60 mg/kg significantly reduced the number of animal contortions by 43.1, 50.1 and 71.3%, respectively.BmoLL leukocyte migration was significantly reduced; in mice treated with \ASA\ the decrease in leukocyte migration was similar to 15 mg/kg of the lectin. BmoLL at doses of 15, 30 and 60 mg/kg significantly reduced the number of animal contortions by 43.1, 50.1 and 71.3%, respectively. The lectin (30 and 60 mg/kg) showed a significant effect in the hot plate assay. BmoLL anti-inflammatory and antinociceptive effects were dose-dependent. The search for new and natural compounds, with minimal side effects, to control pain and inflammation, is constantly increasing. BmoLL has great potential as a natural anti-inflamatory product that can be explored for pharmacological purposes.

Real-Time decision support using data mining to predict blood pressure critical events in intensive medicine patients

Patient blood pressure is an important vital signal to the physicians take a decision and to better understand the patient condition. In Intensive Care Units is possible monitoring the blood pressure due the fact of the patient being in continuous monitoring through bedside monitors and the use of sensors. The intensivist only have access to vital signs values when they look to the monitor or consult the values hourly collected. Most important is the sequence of the values collected, i.e., a set of highest or lowest values can signify a critical event and bring future complications to a patient as is Hypotension or Hypertension. This complications can leverage a set of dangerous diseases and side-effects. The main goal of this work is to predict the probability of a patient has a blood pressure critical event in the next hours by combining a set of patient data collected in real-time and using Data Mining classification techniques. As output the models indicate the probability (%) of a patient has a Blood Pressure Critical Event in the next hour. The achieved results showed to be very promising, presenting sensitivity around of 95%.

Cardiac Damage from Chronic Use of Chloroquine: A Case Report and Review of the Literature

Chloroquine has been widely used in rheumatological treatment, but potential severe side effects require careful follow-up. Cardiac damage is not a common consequence, but its clinical relevance has not yet been described. We report the case of a 58-year-old woman with rheumatoid arthritis, in whom chronic chloroquine use resulted in major irreversible cardiac damage. She presented with syncopal episodes due to complete atrioventricular block confirmed by electrophysiological study whose changes were concluded to be irreversible and a permanent pacemaker was indicated. Endomyocardial biopsy was also performed to search for histopathological and ultrastructural cardiac damage. We also reviewed the 22 cases of chloroquine-induced cardiopathy described to date as well as its pathophysiology.

Effect of Pitavastatin on Vascular Reactivity in Hypercholesterolemic Rabbits

Background: Pitavastatin is the newest statin available in Brazil and likely the one with fewer side effects. Thus, pitavastatin was evaluated in hypercholesterolemic rabbits in relation to its action on vascular reactivity. Objective: To assess the lowest dose of pitavastatin necessary to reduce plasma lipids, cholesterol and tissue lipid peroxidation, as well as endothelial function in hypercholesterolemic rabbits. Methods: Thirty rabbits divided into six groups (n = 5): G1 - standard chow diet; G2 - hypercholesterolemic diet for 30 days; G3 - hypercholesterolemic diet and after the 16th day, diet supplemented with pitavastatin (0.1 mg); G4 - hypercholesterolemic diet supplemented with pitavastatin (0.25 mg); G5 - hypercholesterolemic diet supplemented with pitavastatin (0.5 mg); G6 - hypercholesterolemic diet supplemented with pitavastatin (1.0 mg). After 30 days, total cholesterol, HDL, triglycerides, glucose, creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) were measured and LDL was calculated. In-depth anesthesia was performed with sodium thiopental and aortic segments were removed to study endothelial function, cholesterol and tissue lipid peroxidation. The significance level for statistical tests was 5%. Results: Total cholesterol and LDL were significantly elevated in relation to G1. HDL was significantly reduced in G4, G5 and G6 when compared to G2. Triglycerides, CK, AST, ALT, cholesterol and tissue lipid peroxidation showed no statistical difference between G2 and G3-G6. Significantly endothelial dysfunction reversion was observed in G5 and G6 when compared to G2. Conclusion: Pitavastatin starting at a 0.5 mg dose was effective in reverting endothelial dysfunction in hypercholesterolemic rabbits.

New Exercise-Dipyridamole Combined Test for Nuclear Cardiology in Insufficient Effort: Appropriate Diagnostic Sensitivity Keeping Exercise Prognosis

AbstractBackground:Myocardial perfusion scintigraphy (MPS) in patients not reaching 85% of the maximum predicted heart rate (MPHR) has reduced sensitivity.Objectives:In an attempt to maintain diagnostic sensitivity without losing functional exercise data, a new exercise and dipyridamole combined protocol (EDCP) was developed. Our aim was to evaluate the feasibility and safety of this protocol and to compare its diagnostic sensitivity against standard exercise and dipyridamole protocols.Methods:In patients not reaching a sufficient exercise (SE) test and with no contraindications, 0.56 mg/kg of dipyridamole were IV administered over 1 minute simultaneously with exercise, followed by 99mTc-MIBI injection.Results:Of 155 patients, 41 had MPS with EDCP, 47 had a SE test (≥ 85% MPHR) and 67 underwent the dipyridamole alone test (DIP). They all underwent coronary angiography within 3 months. The three stress methods for diagnosis of coronary lesions had their sensitivity compared. For stenosis ≥ 70%, EDCP yielded 97% sensitivity, SE 90% and DIP 95% (p = 0.43). For lesions ≥ 50%, the sensitivities were 94%, 88% and 95%, respectively (p = 0.35). Side effects of EDCP were present in only 12% of the patients, significantly less than with DIP (p < 0.001).Conclusions:The proposed combined protocol is a valid and safe method that yields adequate diagnostic sensitivity, keeping exercise prognostic information in patients unable to reach target heart rate, with fewer side effects than the DIP.

Cardiac Sympathetic Hyperactivity after Chemotherapy: Early Sign of Cardiotoxicity?

Background:Chemotherapy with anthracyclines and trastuzumab can cause cardiotoxicity. Alteration of cardiac adrenergic function assessed by metaiodobenzylguanidine labeled with iodine-123 (123I-mIBG) seems to precede the drop in left ventricular ejection fraction.Objective:To evaluate and to compare the presence of cardiovascular abnormalities among patients with breast cancer undergoing chemotherapy with anthracyclines and trastuzumab, and only with anthracycline.Methods:Patients with breast cancer were analyzed clinical, laboratory, electrocardiographic and echocardiographic and cardiac sympathetic activity. In scintigraphic images, the ratio of 123I-mIBG uptake between the heart and mediastinum, and the washout rate were calculated. The variables were compared between patients who received anthracyclines and trastuzumab (Group 1) and only anthracyclines (Group 2).Results:Twenty patients, with mean age 57 ± 14 years, were studied. The mean left ventricular ejection fraction by echocardiography was 67.8 ± 4.0%. Mean washout rate was 28.39 ± 9.23% and the ratio of 123I-mIBG uptake between the heart and mediastinum was 2.07 ± 0.28. Of the patients, 82% showed an increased in washout rate, and the ratio of 123I-mIBG uptake between the heart and mediastinum decreased in 25%. Concerning the groups, the mean washout rate of Group 1 was 32.68 ± 9.30% and of Group 2 was 24.56 ± 7.72% (p = 0,06). The ratio of 123I-mIBG uptake between the heart and mediastinum was normal in all patients in Group 2, however, the Group 1, showed 50% the ratio of 123I-mIBG uptake between the heart and mediastinum ≤ 1.8 (p = 0.02).Conclusion:In women with breast cancer undergoing chemotherapy, assessment of cardiac sympathetic activity with 123I-mIBG appears to be an early marker of cardiotoxicity. The combination of chemotherapy showed higher risk of cardiac adrenergic hyperactivity.

New business formation and employment growth: some evidence for the Spanish manufacturing industry

This paper explores the effects of new business formation on employment growth in Spanish manufacturing industries. New firms are believed to make an important contribution to economic growth but the extent of this contribution is unclear. We consider time lags of new firm formation as explanatory variables of employment change and identify how long the effect of new firm entries on employment lasts. Our main results show that the effects of new business formation are positive in the short term, negative in the medium term and positive in the long term, thus confirming the existence of indirect supply-side effects found in similar studies for other countries. Key words: regional growth, firm entry, time lags and Spanish economy. JEL classifications: L00, L60, R11, R12

Implicaciones del uso de fuentes exógenas de fitasa sobre los rendimientos productivos y valor nutricional de las dietas en aves. Repercusiones medioambientales

En los últimos años, y debido a un aumento de las producciones intensivas de cerdos y aves en el marco de la UE, se han desarrollado muchos estudios intentando minimizar el impacto contaminante del exceso de nitrógeno y fósforo que las deyecciones de estos animales producen en el medio ambiente. La disminución del contenido de N procedente de las deyecciones se ha abordado con diferentes estrategias nutricionales (formulación con aminoácidos disponibles, mejora de la utilización de la proteína con diferentes enzimas, etc.). El fósforo es un mineral imprescindible para el crecimiento de los animales, debido a su influencia en el ciclo energético, en la formación de huesos y como regulador de la ingesta. El fósforo presente en los vegetales (base de la alimentación de las aves) se encuentra básicamente formando el ácido fítico, muy poco asimilable por los animales. Por tal motivo, se suplementan las dietas con fósforo inorgánico, a menudo en exceso, que en parte revierte al medio ambiente, dando lugar a problemas medioambientales en áreas de gran concentración de producciones intensivas de animales. En la ultima década se ha estudiado el efecto que la incorporación de la enzima fitasa produce en el aumento de la biodisponibilidad del fósforo fítico (Kornegay et al., 1996), con lo que se reduce la cantidad de fósforo inorgánico añadido a las dietas y, por tanto, la disminución del fósforo excretado. Se ha descrito que la incorporación de este enzima produce ademas mejoras de la disponibilidad de otros minerales (calcio, zinc, cobre, hierro, etc.) (Broz et al., 1994; Schoner et al., 1991; Roberson and Edwards, 1994; Yi et al., 1997; Sebastian et al., 1996), pero dependientes del nivel de calcio y de vitamina D3 (Qian et al., 1996; Qian et al., 1997; Edwards, 1993; Lei et al., 1994), y de la fuente de fibra (Ravindran et al. 1995). También se han descrito mejoras en la digestibilidad de la proteína y los aminoácidos (Yi et al., 1996a; Mroz et al., 1994) , aunque en este campo existe cierta controversia, ya que la respuesta depende de la cantidad y procedencia del ácido fitico de la dieta (O’Dell and Boland, 1976). Sin embargo, casi todos los ensayos se han realizado con dietas a base de maíz-soja, en tanto que a nivel de la UE cada vez más se utilizan otro tipo de ingredientes para las raciones (trigo, cebada, girasol, guisantes, subproductos, etc.). Algunos de estos ingredientes se caracterizan por tener una actividad fitasa endógena nada despreciable (Eeckout and De Paepe, 1994) que, en general, no se ha tenido en cuenta, pero que puede verse afectada en los procesos de granulación. Por otro lado, los efectos beneficiosos de la adición de fitasa a las dietas parecen ser, en ocasiones, más importantes en los aumentos de consumo y mejores índices de conversión que en los derivados de la propia liberación del fósforo, es decir, en los llamados “side effects”, (básicamente, mejora de parámetros productivos, del valor de energía de las dietas, de la utilización de diversos minerales, y de la proteína), aunque existe una gran controversia en algunos de estos efectos. Existen muy pocos estudios sobre el papel de la fibra y otros hidratos de carbono en la actuación de estos enzima (interacción positiva o negativa).

Impact of genetic SLC28 transporter and ITPA variants on ribavirin 21 serum level, hemoglobin drop and therapeutic response in patients with HCV infection

Background: T reatment o f chronic hepatitis C i s evolving, a nd direct acting antivirals ( DAAs) are now a dded to p egylated interferon-α ( Peg- INF-α) and ribavirin (RBV) for the treatment o f hepatitis C v irus ( HCV) genotype 1 infection. DAAs c ause d ifferent side effects and can even worsen RBV induced hemolytic anemia. T herefore, identifying host genetic d eterminants of R BV bioavailability and therapeutic e fficacy will remain crucial for individualized treatment. Recent d ata showed associations between R BV induced h emolytic anemia and genetic polymorphisms o f concentrative nucleoside transporters s uch as C NT3 (SLC28A3) and i nosine t riphosphatase (ITPA). T o analyze t he association of genetic variants of SLC28 transporters and ITPA with RBV induced hemolytic anemia and treatment o utcome. Methods: I n our study, 173 patients f rom t he S wiss Hepatitis C C ohort Study and 2 2 patients from Swiss Association for the Study of the Liver study 24 (61% HCV g enotype 1, 3 9% genotypes 2 o r 3) were analyzed for SLC28A2 single nucleotide p olymorphism (SNP) rs11854484, SLC28A3 rs56350726 and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101. RBV serum levels during treatment were measured in 49 patients. Results: SLC28A2 r s11854484 genotype TT was associated with significantly higher dosage- and body weight-adjusted RBV levels as compared to genotypes TC and CC (p=0.04 and p=0.02 at weeks 4 and 8, respectively). ITPA SNPs rs1127354 and rs7270101 were associated with h emolytic a nemia both in genotype as w ell as i n allelic a nalyses. SLC28A3 rs56350726 genotype TT (vs. AT/AA, RR=2.1; 95% CI 1.1-4.1) as well as the T allele (vs. A; RR=1.8, 95% CI 1.1-3.2) were associated with increased SVR rates. The combined analysis of overall ITPA activity and SLC28 v ariants together revealed n o significant a dditive effects on either treatment-related anemia or SVR. Conclusions: T he newly identified association between RBV serum levels a nd SLC28A2 rs11854484 genotype as well as the replicated association of ITPA and SLC28A3 g enetic p olymorphisms w ith RBV induced hemolytic anemia and treatment r esponse underpin the need for further studies on host genetic d eterminants of R BV bioavailability and therapeutic e fficacy f or individualized treatment of chronic hepatitis C.

Promise for plant pest control: root-associated pseudomonads with insecticidal activities.

Insects are an important and probably the most challenging pest to control in agriculture, in particular when they feed on belowground parts of plants. The application of synthetic pesticides is problematic owing to side effects on the environment, concerns for public health and the rapid development of resistance. Entomopathogenic bacteria, notably Bacillus thuringiensis and Photorhabdus/Xenorhabdus species, are promising alternatives to chemical insecticides, for they are able to efficiently kill insects and are considered to be environmentally sound and harmless to mammals. However, they have the handicap of showing limited environmental persistence or of depending on a nematode vector for insect infection. Intriguingly, certain strains of plant root-colonizing Pseudomonas bacteria display insect pathogenicity and thus could be formulated to extend the present range of bioinsecticides for protection of plants against root-feeding insects. These entomopathogenic pseudomonads belong to a group of plant-beneficial rhizobacteria that have the remarkable ability to suppress soil-borne plant pathogens, promote plant growth, and induce systemic plant defenses. Here we review for the first time the current knowledge about the occurrence and the molecular basis of insecticidal activity in pseudomonads with an emphasis on plant-beneficial and prominent pathogenic species. We discuss how this fascinating Pseudomonas trait may be exploited for novel root-based approaches to insect control in an integrated pest management framework.

RADIC II: a fault tolerant architecture with flexible dynamic redundancy

The demand for computational power has been leading the improvement of the High Performance Computing (HPC) area, generally represented by the use of distributed systems like clusters of computers running parallel applications. In this area, fault tolerance plays an important role in order to provide high availability isolating the application from the faults effects. Performance and availability form an undissociable binomial for some kind of applications. Therefore, the fault tolerant solutions must take into consideration these two constraints when it has been designed. In this dissertation, we present a few side-effects that some fault tolerant solutions may presents when recovering a failed process. These effects may causes degradation of the system, affecting mainly the overall performance and availability. We introduce RADIC-II, a fault tolerant architecture for message passing based on RADIC (Redundant Array of Distributed Independent Fault Tolerance Controllers) architecture. RADIC-II keeps as maximum as possible the RADIC features of transparency, decentralization, flexibility and scalability, incorporating a flexible dynamic redundancy feature, allowing to mitigate or to avoid some recovery side-effects.