Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives.

Chronic intake of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing gastrointestinal tumors, in particular colon cancer. Increasing evidence indicates that NSAID exert tumor-suppressive activity on pre-malignant lesions (polyps) in humans and on established experimental tumors in mice. Some of the tumor-suppressive effects of NSAIDs depend on the inhibition of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxane, which is highly expressed in inflammation and cancer. Recent findings indicate that NSAIDs exert their anti-tumor effects by suppressing tumor angiogenesis. The availability of COX-2-specific NSAIDs opens the possibility of using this drug class as anti-angiogenic agents in combination with chemotheapy or radiotherapy for the treatment of human cancer. Here we will briefly review recent advances in the understanding of the mechanism by which NSAIDs suppress tumor angiogenesis and discuss their potential clinical application as anti-cancer agents.

Low concentrations of 3-hydroxy glutarate leads to ammonium accumulation and non-apoptotic cell death in developing brain cells

We previously showed in a 3D rat brain cell in vitro model for glutaric aciduria type-I that repeated application of 1mM 3-hydroxy-glutarate (3-OHGA) caused ammonium accumulation, morphologic alterations and induction of non-apoptotic cell death in developing brain cells. Here, we performed a dose-response study with lower concentrations of 3- OHGA.We exposed our cultures to 0.1, 0.33 and 1mM 3-OHGA every 12h over three days at two developmental stages (DIV5-8 and DIV11-14). Ammonium accumulation was observed at both stages starting from 0.1mM 3-OHGA, in parallel with a glutamine decrease. Morphological changes started at 0.33mM with loss of MBP expression and loss of astrocytic processes. Neurons were not substantially affected. At DIV8, release of LDH in the medium and cellular TUNEL staining increased from 0.1mM and 0.33mM 3-OHGA exposure, respectively. No increase in activated caspase-3 was observed. We confirmed ammonium accumulation and non-apoptotic cell death of brain cells in our in vitro model at lower 3-OHGA concentrations thus strongly suggesting that the observed effects are likely to take place in the brain of affected patients. The concomitant glutamine decrease suggests a defect in the astrocyte ammonium buffering system. Ammonium accumulation might be the cause of non-apoptotic cell death.

Steady-state global optimization of metabolic non-linear dynamic models through recasting into power-law canonical models

Background: Design of newly engineered microbial strains for biotechnological purposes would greatly benefit from the development of realistic mathematical models for the processes to be optimized. Such models can then be analyzed and, with the development and application of appropriate optimization techniques, one could identify the modifications that need to be made to the organism in order to achieve the desired biotechnological goal. As appropriate models to perform such an analysis are necessarily non-linear and typically non-convex, finding their global optimum is a challenging task. Canonical modeling techniques, such as Generalized Mass Action (GMA) models based on the power-law formalism, offer a possible solution to this problem because they have a mathematical structure that enables the development of specific algorithms for global optimization. Results: Based on the GMA canonical representation, we have developed in previous works a highly efficient optimization algorithm and a set of related strategies for understanding the evolution of adaptive responses in cellular metabolism. Here, we explore the possibility of recasting kinetic non-linear models into an equivalent GMA model, so that global optimization on the recast GMA model can be performed. With this technique, optimization is greatly facilitated and the results are transposable to the original non-linear problem. This procedure is straightforward for a particular class of non-linear models known as Saturable and Cooperative (SC) models that extend the power-law formalism to deal with saturation and cooperativity. Conclusions: Our results show that recasting non-linear kinetic models into GMA models is indeed an appropriate strategy that helps overcoming some of the numerical difficulties that arise during the global optimization task.

Delivery of European Cross-Border Health Care and the Relevance and Effects of EU Regulations and Judicial Processes with Reference to Delivery of Drugs and Blood Donor Information Material.

Valtion rajat ylittävät terveyspalvelut Euroopan unionissa sekä Euroopan unionin säädösten merkitys ja vaikutus erityisesti lääkejakeluun ja verenluovuttajille jaettavaan tiedotusaineistoon Valtion rajat ylittävä terveydenhuolto on suuren kiinnostuksen kohteena Euroopan unionissa. Resurssien hyödyntäminen parhaalla mahdollisella tavalla ja tiedon keskittäminen ovat tarpeen terveydenhuollon kustannusten alati noustessa. Terveydenhuoltopalvelut kuuluvat Euroopan sisämarkkinoiden vapaan liikkuvuuden piiriin. Euroopan unionilla ei ole kuitenkaan toimivaltaa säädellä terveydenhuoltojärjestelmiä, vaan sen mahdollisuudet ovat enimmäkseen kansanterveyden edistämisessä ja suojelussa, myös muilla toimialueilla kuin terveydenhuollossa. Tutkimuksen tavoitteena oli tutkia Euroopan unionin säädösten vaikutusta terveydenhuoltosektoriin, erityisesti valtion rajat ylittäviin terveydenhuoltopalveluihin. Erityiskohteena olivat lääkemääräyksen toimittaminen toisen Euroopan unionin jäsenmaan apteekista, resepti-lääkkeiden maahantuonti omaan henkilökohtaiseen käyttöön, sähköisen lääkemääräyksen käyttö kansallisesti ja mahdollisuudet sen käyttöön eri jäsenmaiden välillä, online-apteekkien soveltuvuus Euroopan unionin sisämarkkinoille sekä verenluovuttajille jaettavan tiedotusaineiston yhtenäistämistarve Euroopan unionin alueella. Tutkimuksen osa-alueiden aineisto koottiin vuosina 1999–2003, jolloin Euroopan unioniin kuului 15 jäsenmaata. Apteekit toimittivat useimmiten myös ei-kansalliset, toisessa Euroopan unionin jäsenmaassa annetut lääkemääräykset. Kaikki jäsenmaat rajoittivat lääkemääräyksen vaativien lääkkeiden maahantuontia. Rajoituksia oli maahantuontimäärissä ja -tavoissa. Lisäksi sairasvakuutuskorvausten saaminen ulkomailla lunastetuista reseptilääkkeistä oli hankalaa. Sähköiset lääkemääräykset olivat käytössä vain kahdessa maassa, mutta useissa maissa suunniteltiin niiden kokeilua. Standardit ja käyttöjärjestelmät olivat erilaisia eri maissa. Euroopan unionin alueelle on perustettu online-apteekkeja, joiden toiminta on kuitenkin vaatimatonta. Verenluovuttajille annettava tiedotusaineisto ei missään maassa täyttänyt veridirektiivin vaatimuksia. Tutkimuksen tulokset osoittivat kansallisten käytäntöjen eroavaisuuksien rajoittavan valtion rajat ylittäviä terveydenhuoltopalveluita. Vaikka Euroopan unionin tavoitteena ei ole yhtenäistää terveydenhuoltojärjestelmiä, on tarpeen arvioida uudelleen unionin ja jäsenmaiden välistä työnjakoa. Kansalliset terveydenhuoltojärjestelmät eivät ole erillään Euroopan sisämarkkinoista, jotka merkittävästi vaikuttavat terveydenhuoltoon.

When the non-contrast-enhanced phase is unnecessary in abdominal computed tomography scans? A retrospective analysis of 244 cases

Objective: To evaluate the necessity of the non contrast-enhanced phase in abdominal computed tomography scans. Materials and Methods: A retrospective, cross-sectional, observational study was developed, evaluating 244 consecutive abdominal computed tomography scans both with and without contrast injection. Initially, the contrast-enhanced images were analyzed (first analysis). Subsequently, the observers had access to the non-contrast-enhanced images for a second analysis. The primary and secondary diagnoses were established as a function of the clinical indications for each study (such as tumor staging, acute abdomen, investigation for abdominal collection and hepatocellular carcinoma, among others). Finally, the changes in the diagnoses resulting from the addition of the non-contrast-enhanced phase were evaluated. Results: Only one (0.4%; p > 0.999; non-statistically significant) out of the 244 reviewed cases had the diagnosis changed after the reading of non-contrast-enhanced images. As the secondary diagnoses are considered, 35 (14%) cases presented changes after the second analysis, as follows: nephrolithiasis (10%), steatosis (3%), adrenal nodule (0.7%) and cholelithiasis (0.3%). Conclusion: For the clinical indications of tumor staging, acute abdomen, investigation of abdominal collections and hepatocellular carcinoma, the non-contrast-enhanced phase can be excluded from abdominal computed tomography studies with no significant impact on the diagnosis.

Digital evidence, 'absence' of data and ambiguous patterns of reasoning

In this paper we discuss the use of digital data by the Swiss Federal Criminal Court in a recent case of attempted homicide. We use this case to examine drawbacks for the defense when the presentation of scientific evidence is partial, especially when the only perspective mentioned is that of the prosecution. We tackle this discussion at two distinct levels. First, we pursue an essentially non-technical presentation of the topic by drawing parallels between the court's summing up of the case and flawed patterns of reasoning commonly seen in other forensic disciplines, such as DNA and particle traces (e.g., gunshot residues). Then, we propose a formal analysis of the case, using elements of probability and graphical probability models, to justify our main claim that the partial presentation of digital evidence poses a risk to the administration of justice in that it keeps vital information from the defense. We will argue that such practice constitutes a violation of general principles of forensic interpretation as established by forensic science literature and current recommendations by forensic science interest groups (e.g., the European Network of Forensic Science Institutes). Finally, we posit that argument construction and analysis using formal methods can help replace digital evidence appropriately into context and thus support a sound evaluation of the evidence.

Evanescent field of vectorial highly non-paraxial beams

In terms of the Fourier spectrum, a simple but general analytical expression is given for the evanescent field associated to a certain kind of non-paraxial exact solutions of the Maxwell equations. This expression enables one to compare the relative weight of the evanescent wave with regard to the propagating field. In addition, in those cases in which the evanescent term is significant, the magnitude of the field components across the transverse profile (including the evanescent features) can be determined. These results are applied to some illustrative examples.

Utilization of retention chemicals in non-wood containing furnishes

The usage of the non-wood pulps in furnishes for various paper grades is the real alternative for substitution of wood fibres in the papermaking. This is especially important now, when the prices for wood are increasing and forest resources are depleting in many regions of our planet. However, there are several problems associated with utilization of such pulps. In terms of the papermaking process one of the main problems is the poor dewatering of the non-wood pulps. This problem can be partially solved by means of retention aids. In the literature part were described technological features of the non-wood pulps as the raw materials for paper production. Moreover, overviews of the retention chemicals and methods for retention measurement were done; special attention was paid to the mechanisms of retention and drainage. Finally, factors affecting on the drainage and retention of non-wood pulps were considered holistically. Particular emphasis was put on the possibility of enzyme treatment for drainage improvement. It was stated that retention aids can significantly improve dewatering of non-wood pulps. In the experimental part the goal was to investigate influence of various microparticle retention aids on the drainage, retention and formation of furnish containing wheat straw pulp, obtained by novel pulping process (Formico™Fib). The parallel test were performed with reference furnish containing only wood pulps. It was found that Bentonite-CPAM retention aid can significantly improve drainage and retention; however formation seems be suffer from such additives. It was stated that performance of the Silica-Starch retention aid significantly depends on the starch dosing sequence and wet-end conditions; this system have shown better formation than other tested retention aids. Silica-CPAM retention aid have provided comparable results in retention and drainage with Bentonite-CPAM, while Silica-starch did not improve dewatering and yielded in lowest filler retention among other aids. Ultimately, optimal dosages for the tested retention chemicals have been suggested.

Control of Structures with Cubic and Quadratic Non-Linearities with Time Delay Consideration

This paper studies the effect of time delay on the active non-linear control of dynamically loaded flexible structures. The behavior of non-linear systems under state feedback control, considering a fixed time delay for the control force, is investigated. A control method based on non-linear optimal control, using a tensorial formulation and state feedback control is used. The state equations and the control forces are expressed in polynomial form and a performance index, quadratic in both state vector and control forces, is used. General polynomial representations of the non-linear control law are obtained and implemented for control algorithms up to the fifth order. This methodology is applied to systems with quadratic and cubic non-linearities. Strongly non-linear systems are tested and the effectiveness of the control system including a delay for the application of control forces is discussed. Numerical results indicate that the adopted control algorithm can be efficient for non-linear systems, chiefly in the presence of strong non-linearities but increasing time delay reduces the efficiency of the control system. Numerical results emphasize the importance of considering time delay in the project of active structural control systems.

Carryover of Imazethapyr + Imazapic on Ryegrass and Non-tolerant Rice as Affected by Thickness of Soil Profile

Herbicides used in Clearfield(r) rice system may persist in the environment, damaging non-tolerant crops sown in succession and/or rotation. These damages vary according to soil characteristics, climate and soil management. The thickness of the soil profile may affect carryover effect; deeper soils may allow these molecules to leach, reaching areas below the roots absorption zone. The aim of this study was to evaluate the effect of the thickness of soil profile in the carryover of imazethapyr + imazapic on ryegrass and non-tolerant rice, sown in succession and rotation to rice, respectively. Lysimeters of different thicknesses (15, 20, 30, 40, 50 and 65 cm) were constructed, where 1 L ha-1 of the imazethapyr + imazapic formulated mixture was applied in tolerant rice. Firstly, imidazolinone-tolerant rice was planted, followed by ryegrass and non-tolerant rice in succession and rotation, respectively. Herbicide injury, height reduction and dry weight of non-tolerant species were assessed. There was no visual symptoms of herbicide injury on ryegrass sown 128 days after the herbicide application; however it causes dry weight mass reduction of plants. The herbicides persist in the soil and cause injury in non-tolerant rice, sown 280 days after application, and the deeper the soil profile, the lower the herbicides injury on irrigated rice.

Modelling of ultrasound assisted mixing in Newtonian and non-Newtonian liquids

The purpose of this work is to obtain a better understanding of behaviour of possible ultrasound appliance on fluid media mixing. The research is done in the regard to Newtonian and non-Newtonian fluids. The process of ultrasound appliance on liquids is modelled in COMSOL Multiphysics software. The influence of ultrasound using is introduced as waveform equation. Turbulence modelling is fulfilled by the k-ε model in Newtonian fluid. The modeling of ultrasound assisted mixing in non-Newtonian fluids is based on the power law. To verify modelling results two practical methods are used: Particle Image Velocimetry and measurements of mixing time. Particle Image Velocimetry allows capturing of velocity flow field continuously and presents detailed depiction of liquid dynamics. The second way of verification is the comparison of mixing time of homogeneity. Experimentally achievement of mixing time is done by conductivity measurements. In modelling part mixing time is achieved by special module of COMSOL Multiphysics – the transport of diluted species. Both practical and modelling parts show similar radial mechanism of fluid flow under ultrasound appliance – from the horn tip fluid moves to the bottom and along the walls goes back. Velocity profiles are similar in modelling and experimental part in the case of Newtonian fluid. In the case of non-Newtonian fluid velocity profiles do not agree. The development track of ultrasound-assisted mixing modelling is presented in the thesis.

Working fluid selection and design of small-scale waste heat recovery systems based on organic Rankine cycles

Demand for the use of energy systems, entailing high efficiency as well as availability to harness renewable energy sources, is a key issue in order to tackling the threat of global warming and saving natural resources. Organic Rankine cycle (ORC) technology has been identified as one of the most promising technologies in recovering low-grade heat sources and in harnessing renewable energy sources that cannot be efficiently utilized by means of more conventional power systems. The ORC is based on the working principle of Rankine process, but an organic working fluid is adopted in the cycle instead of steam. This thesis presents numerical and experimental results of the study on the design of small-scale ORCs. Two main applications were selected for the thesis: waste heat re- covery from small-scale diesel engines concentrating on the utilization of the exhaust gas heat and waste heat recovery in large industrial-scale engine power plants considering the utilization of both the high and low temperature heat sources. The main objective of this work was to identify suitable working fluid candidates and to study the process and turbine design methods that can be applied when power plants based on the use of non-conventional working fluids are considered. The computational work included the use of thermodynamic analysis methods and turbine design methods that were based on the use of highly accurate fluid properties. In addition, the design and loss mechanisms in supersonic ORC turbines were studied by means of computational fluid dynamics. The results indicated that the design of ORC is highly influenced by the selection of the working fluid and cycle operational conditions. The results for the turbine designs in- dicated that the working fluid selection should not be based only on the thermodynamic analysis, but requires also considerations on the turbine design. The turbines tend to be fast rotating, entailing small blade heights at the turbine rotor inlet and highly supersonic flow in the turbine flow passages, especially when power systems with low power outputs are designed. The results indicated that the ORC is a potential solution in utilizing waste heat streams both at high and low temperatures and both in micro and larger scale appli- cations.

Effectiveness of highly active antiretroviral therapy using non-brand name drugs in Brazil

In Brazil, HIV-infected individuals receive drugs (including non-brand name drugs which comprise locally produced generics and drugs that have not been tested in bioequivalence trials) free of charge from the government. The objective of the present study was to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in Rio de Janeiro, Brazil, where non-brand drugs are widely used. For this purpose, we estimated the proportion of subjects with virologic failure (plasma HIV viral load greater than 400 copies/mL at 6 months after initiation of treatment). This was a retrospective cohort study of drug-naive HIV-infected subjects who initiated HAART. Subjects were included in the analysis if they were 18 years of age or older, were treatment naive, started HAART with a minimum of 3 drugs, and had available information on blood plasma HIV-1 viral load after 6 months on therapy. All subjects used antiretrovirals in dosing regimens recommended by the Brazilian National Advisory Committee for Antiretroviral Therapy. Chart reviews were conducted in three settings: at two public health outpatient units, at one clinical trial unit and at one private office. No comparisons of the effectiveness of non-brand name with the effectiveness of brand name drugs were made. We present results for 485 patients; of these, 354 (73%), 55 (11%), and 76 (16%) were seen at the public health outpatient units, private office, and clinical trial unit, respectively. Virologic failure was observed in 119 (25%) of the subjects. This study demonstrates the effectiveness of HAART in a setting where non-brand name drugs are widely used.

Defensive responses to threat scenarios in Brazilians reproduce the pattern of Hawaiian Americans and non-human mammals

A former study with scenarios conducted in Hawaii has suggested that humans share with non-human mammals the same basic defensive strategies - risk assessment, freezing, defensive threat, defensive attack, and flight. The selection of the most adaptive strategy is strongly influenced by features of the threat stimulus - magnitude, escapability, distance, ambiguity, and availability of a hiding place. Aiming at verifying if these strategies would be consistent in a different culture, 12 defensive scenarios were translated into Portuguese and adapted to the Brazilian culture. The sample consisted of male and female undergraduate students divided into two groups: 76 students, who evaluated the five dimensions of each scenario and 248 medical students, who chose the most likely response for each scenario. In agreement with the findings from studies of non-human mammal species, the scenarios were able to elicit different defensive behavioral responses, depending on features of the threat. "Flight" was chosen as the most likely response in scenarios evaluated as an unambiguous and intense threat, but with an available route of escape, whereas "attack" was chosen in an unambiguous, intense and close dangerous situation without an escape route. Less urgent behaviors, such as "check out", were chosen in scenarios evaluated as less intense, more distant and more ambiguous. Moreover, the results from the Brazilian sample were similar to the results obtained in the original study with Hawaiian students. These data suggest that a basic repertoire of defensive strategies is conserved along the mammalian evolution because they share similar functional benefits in maintaining fitness.

Effect of sugar and water contents on non-expanded cassava flour extrudates

The effects of sucrose and water contents on cassava flour processed by extrusion at varied concentrations of sucrose (0-20% w/w) and water (28-42% w/w) were studied by applying response surface methodology. The extrusion of the mixtures was performed in a twin screw extruder fitted to a torque rheometer. The specific mechanical energy (SME) dissipated inside a conical twin-screw extruder was measured. Water absorption index (WAI), water solubility index (WSI) and paste viscosity readings (cold viscosity (CV), peak viscosity (PV), breakdown (BD) and set back (SB)) during a gelatinization-retrogradation cycle measured in a Rapid Visco Analyzer were determined on non-directly extruded products. The results indicated that SME and WSI decreased as a function of water and sucrose contents. WAI and pasting properties were influenced by water content. A non antiplasticizing effect of the sucrose content was observed on pasting properties, suggesting that sucrose did not reduce the availability of water available for gelatinizing cassava flour during the extrusion process. The nature of the optimum point was characterized as a saddle point for WAI, WSI, PV and BD, whereas SME showed a maximum and CV and SB a minimum. The results indicated to be valuable for the production of non-expanded cassava flour extrudates with desirable functional properties for specific end users.