Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone

Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration (Cmax) of 4-methylaminoantipyrine (MAA), an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336), measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC0-¥ and the Cmax of MAA can be accurately predicted (R²>0.95, bias <1.5%, precision between 3.1 and 8.3%) by LSS models based on two sampling times. Validation tests indicate that the most informative 2-point LSS models developed for one formulation provide good estimates (R²>0.85) of the AUC0-¥ or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h), but using different coefficients for AUC0-¥ and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R²>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4%) as well as for plasma concentration data sets generated by simulation (R²>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%). Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC0-¥ and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

Evaluation of behavioral states among morning and evening active healthy individuals

The Horne-Östberg questionnaire partly covers some factors that may be important determinants of peak time and characterize patterns of behavior. We conducted a study for the evaluation of self-reported behavioral states (hunger sensation, availability for study, physical exercise, solving daily problems, and time preferences) as expressions of underlying cyclic activity. Three hundred and eighteen community subjects without history of medical, psychiatric, or sleep disorders were evaluated in a cross-sectional design. A self-report about daily highest level of activity was used to categorize individuals into morning, evening, and indifferently active. Time-related behavioral states were evaluated with 23 visual analog questions. The responses to most analogic questions were significantly different between morning and evening active subjects. Logistic regression analysis identified a group of behaviors more strongly associated with the self-reported activity pattern (common wake up time, highest subjective fatigue, as well as wake up, bedtime, exercise and study preferences). These findings suggested that the patterns of activity presented by normal adults were related to specific common behavioral characteristics that may contribute to peak time.

Chemokines in the cerebrospinal fluid of patients with active and stable relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the human central nervous system. Although its etiology is unknown, the accumulation and activation of mononuclear cells in the central nervous system are crucial to its pathogenesis. Chemokines have been proposed to play a major role in the recruitment and activation of leukocytes in inflammatory sites. They are divided into subfamilies on the basis of the location of conserved cysteine residues. We determined the levels of some CC and CXC chemokines in the cerebrospinal fluid (CSF) of 23 relapsing-remitting MS patients under interferon-ß-1a therapy and 16 control subjects using ELISA. MS patients were categorized as having active or stable disease. CXCL10 was significantly increased in the CSF of active MS patients (mean ± SEM, 369.5 ± 69.3 pg/mL) when compared with controls (178.5 ± 29.1 pg/mL, P < 0.05). CSF levels of CCL2 were significantly lower in active MS (144.7 ± 14.4 pg/mL) than in controls (237.1 ± 16.4 pg/mL, P < 0.01). There was no difference in the concentration of CCL2 and CXCL10 between patients with stable MS and controls. CCL5 was not detectable in the CSF of most patients or controls. The qualitative and quantitative differences of chemokines in CSF during relapses of MS suggest that they may be useful as a marker of disease activity and of the mechanisms involved in the pathogenesis of the disease.

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.

Expression and purification of the immunogenically active fragment B of the Park Williams 8 Corynebacterium diphtheriae strain toxin

The construction of a hexahistidine-tagged version of the B fragment of diphtheria toxin (DTB) represents an important step in the study of the biological properties of DTB because it will permit the production of pure recombinant DTB (rDTB) in less time and with higher yields than currently available. In the present study, the genomic DNA of the Corynebacterium diphtheriae Park Williams 8 (PW8) vaccine strain was used as a template for PCR amplification of the dtb gene. After amplification, the dtb gene was cloned and expressed in competent Escherichia coli M15™ cells using the expression vector pQE-30™. The lysate obtained from transformed E. coli cells containing the rDTB PW8 was clarified by centrifugation and purified by affinity chromatography. The homogeneity of the purified rDTB PW8 was confirmed by immunoblotting using mouse polyclonal anti-diphtheria toxoid antibodies and the immune response induced in animals with rDTB PW8 was evaluated by ELISA and dermonecrotic neutralization assays. The main result of the present study was an alternative and accessible method for the expression and purification of immunogenically reactive rDTB PW8 using commercially available systems. Data also provided preliminary evidence that rabbits immunized with rDTB PW8 are able to mount a neutralizing response against the challenge with toxigenic C. diphtheriae.

Lack of evidence for regulation of cardiac P-type ATPases and MAP kinases in transgenic mice with cardiac-specific overexpression of constitutively active α1B-adrenoceptors

The regulatory function of α1B-adrenoceptors in mammalian heart homeostasis is controversial. The objective of the present study was to characterize the expression/activity of key proteins implicated in cardiac calcium handling (Na+/K+-ATPase and Ca2+-ATPases) and growth (ERK1/2, JNK1/2 and p38) in mice with cardiac-selective overexpression of constitutively active mutant α1B-adrenoceptor (CAMα1B-AR), which present a mild cardiac hypertrophy phenotype. Immunoblot assays showed that myocardial plasma membrane Ca2+-ATPase (PMCA) expression was increased by 30% in CAMα1B-AR mice (N = 6, P < 0.05), although there was no change in sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2) expression. Moreover, total Ca2+-ATPase activity was not modified, but a significant increase in the activity of the thapsigargin-resistant (PMCA) to thapsigargin-sensitive (SERCA) ratio was detected. Neither Na+/K+-ATPase activity nor the expression of α1 and α2 subunit isoforms was changed in CAMα1B-AR mouse hearts. Moreover, immunoblot assays did not provide evidence for an enhanced activation of the three mitogen-activated protein kinases studied in this stage of hypertrophy. Therefore, these findings indicate that chronic cardiac α1B-AR activation in vivo led to mild hypertrophy devoid of significant signs of adaptive modifications concerning primary intracellular calcium control and growth-related proteins, suggesting a minor pathophysiological role of this adrenergic receptor in mouse heart at this stage of development.

Protein turnover, amino acid requirements and recommendations for athletes and active populations

Skeletal muscle is the major deposit of protein molecules. As for any cell or tissue, total muscle protein reflects a dynamic turnover between net protein synthesis and degradation. Noninvasive and invasive techniques have been applied to determine amino acid catabolism and muscle protein building at rest, during exercise and during the recovery period after a single experiment or training sessions. Stable isotopic tracers (13C-lysine, 15N-glycine, ²H5-phenylalanine) and arteriovenous differences have been used in studies of skeletal muscle and collagen tissues under resting and exercise conditions. There are different fractional synthesis rates in skeletal muscle and tendon tissues, but there is no major difference between collagen and myofibrillar protein synthesis. Strenuous exercise provokes increased proteolysis and decreased protein synthesis, the opposite occurring during the recovery period. Individuals who exercise respond differently when resistance and endurance types of contractions are compared. Endurance exercise induces a greater oxidative capacity (enzymes) compared to resistance exercise, which induces fiber hypertrophy (myofibrils). Nitrogen balance (difference between protein intake and protein degradation) for athletes is usually balanced when the intake of protein reaches 1.2 g·kg-1·day-1 compared to 0.8 g·kg-1·day-1 in resting individuals. Muscular activities promote a cascade of signals leading to the stimulation of eukaryotic initiation of myofibrillar protein synthesis. As suggested in several publications, a bolus of 15-20 g protein (from skimmed milk or whey proteins) and carbohydrate (± 30 g maltodextrine) drinks is needed immediately after stopping exercise to stimulate muscle protein and tendon collagen turnover within 1 h.

Intensive chemotherapy as salvage treatment for solid tumors: focus on germ cell cancer

Germ cell tumors present contrasting biological and molecular features compared to many solid tumors, which may partially explain their unusual sensitivity to chemotherapy. Reduced DNA repair capacity and enhanced induction of apoptosis appear to be key factors in the sensitivity of germ cell tumors to cisplatin. Despite substantial cure rates, some patients relapse and subsequently die of their disease. Intensive doses of chemotherapy are used to counter mechanisms of drug resistance. So far, high-dose chemotherapy with hematopoietic stem cell support for solid tumors is used only in the setting of testicular germ cell tumors. In that indication, high-dose chemotherapy is given as the first or late salvage treatment for patients with either relapsed or progressive tumors after initial conventional salvage chemotherapy. High-dose chemotherapy is usually given as two or three sequential cycles using carboplatin and etoposide with or without ifosfamide. The administration of intensive therapy carries significant side effects and can only be efficiently and safely conducted in specialized referral centers to assure optimum patient care outcomes. In breast and ovarian cancer, most studies have demonstrated improvement in progression-free survival (PFS), but overall survival remained unchanged. Therefore, most of these approaches have been dropped. In germ cell tumors, clinical trials are currently investigating novel therapeutic combinations and active treatments. In particular, the integration of targeted therapies constitutes an important area of research for patients with a poor prognosis.

Standing before a sentence : Moore’s paradox and a perspective from within language

Med avstamp i ett satsbegrepp som inspirerats av Ludwig Wittgenstein, där sats och kontext betraktas som internt förbundna och där den verkliga användningen av en sats är central för dess mening, visar avhandlingen hur filosofers olika uppfattning om den filosofiska terminologins roll och möjligheter har följder för deras sätt att uppfatta och behandla filosofiska frågeställningar. Moores paradox fungerar som testfall. Denna kända filosofiska frågeställning har diskuterats sedan 1940-talet och kretsar kring hävdandet av satsen ”Jag tror att det regnar och det regnar inte”. Problemet är att det vore märkligt för en talare att hävda satsen om sig själv: det verkar finnas ett logiskt hinder för att hävda en sats även om den är välformad, kunde vara sann och inte på ett entydigt sätt innehåller en kontradiktion. Moores paradox behandlas genom att granska några lösningsförslag (framförda av bl.a. G.E. Moore, J. L. Austin, J. Searle) och de uppfattningar om språket som de förutsätter. Genom att kontrastera dessa med ett användarperspektiv där språkets användning i meningsfulla sammanhang förväntas spela en central roll i behandlingen av paradoxen visar författaren hur också den intellektuella kontext inom vilken en filosof betraktar paradoxen spelar en avgörande roll för vilka mått som krävs för att upplösa den. Istället för att föreslå en egen lösning presenteras en behandling av paradoxen genom en diskussion och utredning av de grundvillkor som leder till att den uppstår. Här intar satsbegreppet en central plats. Avhandlingen är författad inom traditionen efter den senare Wittgenstein (närmare bestämt den gren som ansluter sig till en s.k. terapeutisk filosofisyn) men går i dialog med filosofiskt arbete som ligger utanför traditionen. Författaren strävar både till att medla mellan, sammanföra och särskilja olika temata som behandlats på ett sätt inom traditionen och på andra sätt utanför den och använder sig här av metaforen att filosofera inifrån i kontrast till utanför språket. Avhandlingens huvudsakliga bidrag är till metafilosofin genom dess fokus på filosofins metod. ------------------------------------------------------------ Mooren paradoksi on tunnettu filosofinen ongelma, josta on keskusteltu 1940-luvulta alkaen. Paradoksin keskeisenä osana esiintyy väitelause ”Uskon, että ulkona sataa, mutta ulkona ei sada”. Ongelman lähtökohta on, että olisi merkillistä jos puhuja esittäisi lauseen itseään koskevana väitteenä: väite näyttää olevan loogisesti mahdoton esittää, vaikka se on hyvinmuodostettu, mahdollisesti tosi, eikä yksiselitteisellä tavalla sisällä kontradiktiota. Tässä väitöskirjassa Mooren paradoksi esiintyy esimerkkinä filosofisesta ongelmasta, jossa mm. lausekäsitteellä on keskeinen rooli ja jonka avulla voidaan muodostella ns. kielensisäinen filosofinen näkökulma. Mooren paradoksia käsitellään tarkastelemalla muutamia ratkaisuehdotuksia (mm. G.E. Mooren, J.L. Austinin, J. Searlen esittämät) ja niitä kielikäsityksiä joita nämä ratkaisuehdotukset edellyttävät. Asettamalla vastakkain ratkaisuehdotukset ja käyttäjänäkymä, jossa kielenkäyttö mielekkäissä konteksteissa asetetaan keskeiseen asemaan paradoksin käsittelyssä, kirjoittaja osoittaa miten myös paradoksin filosofisen tarkastelun intellektuaalinen konteksti on hyväksyttävien toimenpiteiden löytämisen kannalta ratkaisevaa. Uuden ratkaisun sijaan kirjoittaja ehdottaa paradoksin terapeuttista käsittelyä: keskustelua ja selontekoa niistä perusehdoista, jotka johtavat sen syntyyn. Tässä käsittelyssä lausekäsite on keskipisteenä – erityisesti Ludwig Wittgensteinin inspiroima lausekäsitys, jossa lauseen mielekkyyden kannalta sen todellinen käyttö mielekkäässä kontekstissa on ratkaiseva tekijä. Väitöskirja liittyy myöhäisiwittgensteinilaiseen perinteeseen, johon kuuluu ns. terapeuttinen filosofiankäsitys, mutta teos keskustelee myös tradition ulkopuolisten ajattelijoiden kanssa yrittäen yhdistää, sovitella ja myös eritellä teemoja, joita käsitellään yhdellä tavalla tradition sisällä ja toisella tavalla sen ulkopuolella. Väitöskirjan pääasiallinen panos sijoittuu metafilosofiaan, koska sen mielenkiinnon kohteena ovat erityisesti filosofian menetelmät.

Chemical, biochemical, and microbiological aspects of chitosan quaternary salt as active coating on sliced apples

The biocompatibility of chitosan and chitosan quaternary salt coatings was evaluated for use as edible coatings for sliced apple. Measurement of water loss, color change, and fungal growth appearance were monitored as a function of time. A significant brownish effect was observed on chitosan coated slices, varying greatly from L* = 76.5 and Hue angle = 95.9° (t = 0) to L* = 45.3 and Hue angle = 69.8° (t = 3 days), whilst for TMC coated samples the variation was considerable lower (L* = 74.1; Hue angle = 95.0°) to (L* = 67.0; Hue angle = 83.8°) within the same period. The hydrosoluble derivative N,N,N-trimethylchitosan demonstrated good antifungal activity against P. expansum although highly dependent on the polymer properties such as degree of quaternization. The most efficient formulation was that prepared from derivative having a degree of quaternization of 45%, high solubility, and high viscosity. This formulation restrained fungus spreading up to 30%, while for the control it reached almost 80% of the total assessed surfaces during 7 days of storage.

Active Magnetic Bearing System Identification Methods and Rotor Model Updating

Active magnetic bearing is a type of bearing which uses magnetic field to levitate the rotor. These bearings require continuous control of the currents in electromagnets and data from position of the rotor and the measured current from electromagnets. Because of this different identification methods can be implemented with no additional hardware. In this thesis the focus was to implement and test identification methods for active magnetic bearing system and to update the rotor model. Magnetic center calibration is a method used to locate the magnetic center of the rotor. Rotor model identification is an identification method used to identify the rotor model. Rotor model update is a method used to update the rotor model based on identification data. These methods were implemented and tested with a real machine where rotor was levitated with active magnetic bearings and the functionality of the methods was ensured. Methods were developed with further extension in mind and also with the possibility to apply them for different machines with ease.

Relay protection in active distribution networks

Increasingly growing share of distributed generation in the whole electrical power system’s generating system is currently a worldwide tendency, driven by several factors, encircling mainly difficulties in refinement of megalopolises’ distribution networks and its maintenance; widening environmental concerns adding to both energy efficiency approaches and installation of renewable sources based generation, inherently distributed; increased power quality and reliability needs; progress in IT field, making implementable harmonization of needs and interests of different-energy-type generators and consumers. At this stage, the volume, formed by system-interconnected distributed generation facilities, have reached the level of causing broad impact toward system operation under emergency and post-emergency conditions in several EU countries, thus previously implementable approach of their preliminary tripping in case of a fault, preventing generating equipment damage and disoperation of relay protection and automation, is not applicable any more. Adding to the preceding, withstand capability and transient electromechanical stability of generating technologies, interconnecting in proximity of load nodes, enhanced significantly since the moment Low Voltage Ride-Through regulations, followed by techniques, were introduced in Grid Codes. Both aspects leads to relay protection and auto-reclosing operation in presence of distributed generation generally connected after grid planning and construction phases. This paper proposes solutions to the emerging need to ensure correct operation of the equipment in question with least possible grid refinements, distinctively for every type of distributed generation technology achieved its technical maturity to date and network’s protection. New generating technologies are equivalented from the perspective of representation in calculation of initial steady-state short-circuit current used to dimension current-sensing relay protection, and widely adopted short-circuit calculation practices, as IEC 60909 and VDE 0102. The phenomenon of unintentional islanding, influencing auto-reclosing, is addressed, and protection schemes used to eliminate an sustained island are listed and characterized by reliability and implementation related factors, whereas also forming a crucial aspect of realization of the proposed protection operation relieving measures.

O Beethoven-Schrift: Richard Wagner teórico

Quando consideramos a extensão da obra dramática de Richard Wagner, não causa estranheza que seus textos teóricos sejam praticamente desconhecidos. No entanto, um de seus escritos, intitulado Beethoven, influenciou decisivamente a elaboração de um livro famoso, hoje considerado um capítulo importante da história da estética, O nascimento da tragédia. Este artigo pretende analisar este escrito de Wagner na intenção de desvendar o que pode ter sido tão determinante na leitura que Nietzsche fez dele, e que o levou ao ponto de citá-lo de modo efusivo no primeiro prefácio da sua obra de estréia, dedicado àquele que, até então, era seu grande mestre e amigo e, como veremos, uma influência não só musical, mas também teórica.