Saturable metabolism of continuous high-dose ifosfamide with mesna and GM-CSF: a pharmacokinetic study in advanced sarcoma patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide mesna +/- GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. PATIENTS AND METHODS: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. RESULTS: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosuppression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). CONCLUSION: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studies.

Phytochrome interacting factors 4 and 5 redundantly limit seedling de-etiolation in continuous far-red light.

Phytochromes are red/far-red photosensors that regulate numerous developmental programs in plants. Among them, phytochrome A (phyA) is essential to enable seedling de-etiolation under continuous far-red (FR) light, a condition that mimics the environment under a dense canopy. The ecological relevance of this response is demonstrated by the high mortality rate of phyA mutant plants that germinate in deep vegetational shade. phyA signaling involves direct interaction of the photoreceptor with phytochrome-interacting factors PIF1 and PIF3, members of the bHLH transcription factor family. Here we investigated the involvement of PIF4 and PIF5 in phyA signaling, and found that they redundantly control de-etiolation in FR light. The pif4 pif5 double mutant is hypersensitive to low fluence rates of FR light. This phenotype is dependent on FR light perception by phyA, but does not rely on alterations in the phyA level. Our microarray analysis shows that PIF4 and PIF5 are part of an inhibitory mechanism that represses the expression of some light-responsive genes in the dark, and that they are also needed for full expression of several growth-related genes in the light. Unlike PIF1 and PIF3, PIF4 and PIF5 are not degraded in response to FR light, indicating that they are light-regulated by a different mechanism. Our genetic analysis suggests that this is achieved through sequestration of these PIFs by the closely related bHLH transcription factor HFR1 (long hypocotyl in FR light).

Clonal analysis of the BALB/c T cell proliferative response to apo beef cytochrome c.

Murine T cell clones that proliferated specifically in response to the protein antigen apo cytochrome c were derived and maintained in continuous culture. Two distinct clonotypes were observed with respect to the proliferative responses observed when a variety of peptides prepared from several species of cytochrome c were tested. These 2 clonotypes appeared to recognize 2 different regions in the cytochrome c molecule. Only 1 of the 2 clonotypes tested demonstrated helper cell activity for antibody formation in vitro.

Relações solo-vegetação em áreas sob processo de desertificação no município de Jataúba, PE

A degradação das terras na região semi-árida resulta de processos naturais, que podem ser induzidos ou catalisados pelo homem por meio do uso inadequado dos recursos naturais, produzindo a deterioração da cobertura vegetal, do solo e dos recursos hídricos. Visando relacionar os processos de degradação da vegetação e dos solos na zona do agreste de Pernambuco, foram caracterizados os solos e o recobrimento vegetal em doze parcelas representativas de ambientes conservados, moderadamente degradados e degradados, no município de Jataúba. Para caracterizar a vegetação, os indivíduos foram classificados em três estratos verticais ou classes de altura: 3- indivíduos com altura superior a 3,0 m (lenhosas altas), amostrados em toda a área da parcela (200 m²); 2- indivíduos com altura variando de 0,51 a 3,0 m, amostrados em subárea de 100 m² (lenhosas baixas); 1- indivíduos com altura igual ou inferior a 0,5 m, amostrados em 18 miniparcelas de 25 x 50 cm (estrato da regeneração). Os solos de cada parcela foram caracterizados morfologicamente e as amostras coletadas por horizonte para realização das análises físicas, químicas e mineralógicas. A vegetação no segundo estrato vertical apresentou significativa diminuição da densidade absoluta de acordo com a intensidade de degradação dos solos. As espécies com maiores densidades relativas foram: Neoglaziovia variegata (caroá) e Cordia leucocephala (moleque duro), no ambiente conservado; Bromelia laciniosa (macambira), Aspidosperma pyryfolium (pereiro) e Caesalpinia pyramidalis (catingueira), no ambiente moderadamente degradado, e C. pyramidalis e Sida galheirensis (malva branca), no ambiente degradado. As características dos Planossolos mais bem relacionadas com a vegetação preservada foram: os maiores conteúdos de cascalho nos horizontes superficiais, a maior espessura dos horizontes A + E e os teores mais elevados de CO. A ocorrência de encrostamento superficial e erosão e os elevados teores de Na trocável foram observados mais intensamente nos ambientes degradados, sendo mais severos onde a vegetação se encontrava mais esparsa.

Continuous phase shift of sinusoidal signals using injection locked oscillators

This work presents an alternative to generate continuous phase shift of sinusoidal signals based on the use of super harmonic injection locked oscillators (ILO). The proposed circuit is a second harmonic ILO with varactor diodes as tuning elements. In the locking state, by changing the varactor bias, a phase shift instead of a frequency shift is observed at the oscillator output. By combining two of these circuits, relative phases up to 90 could be achieved. Two prototypes of the circuit have been implemented and tested, a hybrid version working in the range of 200-300 MHz and a multichip module (MCM) version covering the 900¿1000 MHz band.

Atributos químicos e microbianos do solo de áreas em processo de desertificação no semiárido de Pernambuco

Devido ao avanço das áreas em processo de degradação decorrente de causas naturais e, ou, influências antrópicas, faz-se necessária a utilização de ferramentas, preferencialmente de baixo custo, que indiquem os estádios dessa degradação, a fim de viabilizar um manejo adequado e a recuperação dessas áreas. Desse modo, o objetivo desta pesquisa foi analisar a variabilidade de atributos químicos e microbianos de solos, visando a utilizá-los como indicadores de processos de desertificação, em áreas sob níveis crescentes de degradação na região semiárida do Estado de Pernambuco. Foram amostrados três ambientes: conservado, moderadamente degradado e intensamente degradado, no município de Floresta-PE. Em cada ambiente foram escolhidas quatro áreas de amostragens e efetuadas sete coletas em cada um delas, totalizando 28 pontos amostrados por ambiente. Foram coletadas amostras de solo na profundidade de 0-10 cm, nos períodos seco e chuvoso. Realizaram-se análises químicas (pH, bases trocáveis, acidez potencial, C orgânico do solo, estoque de C, P disponível e capacidade de troca de cátions) e microbianas (C da biomassa microbiana, respiração basal, quocientes microbiano e metabólico) do solo, além da caracterização física (textura e densidade do solo). Os dados foram analisados adotando-se métodos de análises de componentes principais e teste t. Verificou-se o efeito da sazonalidade para os atributos do solo, sendo essa mudança mais perceptível no ambiente degradado. Com as análises de componentes principais, foi possível destacar alguns atributos mais sensíveis ao avanço da degradação, como o C da biomassa microbiana do solo, a acidez potencial e a saturação por bases, tanto no período seco como no chuvoso. Desse modo, esses atributos podem ser utilizados como indicadores do nível de degradação do solo.

Mean first-passage time of continuous non-Markovian processes driven by colored noise

An equation for mean first-passage times of non-Markovian processes driven by colored noise is derived through an appropriate backward integro-differential equation. The equation is solved in a Bourret-like approximation. In a weak-noise bistable situation, non-Markovian effects are taken into account by an effective diffusion coefficient. In this situation, our results compare satisfactorily with other approaches and experimental data.

Nitrogênio, carbono e compactação do solo como fatores limitantes do processo de recuperação de matas ciliares

A recuperação de áreas de floresta, principalmente de matas ciliares, tornou-se fator-chave para a adequação ambiental da agricultura, com o propósito de proteger os recursos hídricos e a biota. Entretanto, o cultivo agrícola tradicional, além de ter alterado a ciclagem de nutrientes com a perda de matéria orgânica, biomassa e atividade microbiana, causou também a compactação do solo, o que influencia a posterior implantação de reflorestamentos. O objetivo deste trabalho foi identificar quais atributos do solo (físicos, químicos e microbiológicos) mais influenciam o teor de C, N, P e umidade da serapilheira em áreas de mata ciliar com diferentes idades de recuperação (20, 10 e cinco anos), em comparação com uma área nativa (NT). A partir da ANOVA e dos testes de médias (Duncan) e correlação (Pearson), foram verificados quais atributos acompanham o tempo de recuperação e qual a relação entre eles. A análise multivariada de partição da inércia a partir da análise de redundância (pRDA) foi feita a fim de identificar quais atributos do solo foram mais importantes para discriminar entre as áreas, com base nos teores de C, N, P e umidade da serapilheira encontrados nessas áreas. Maior relação C/N da serapilheira foi encontrada nas áreas de 20 (26,8) e de cinco (29,9) anos. Entre os atributos microbiológicos avaliados, observou-se que a respiração basal do solo (C-CO2), o carbono da biomassa microbiana (CBM) e a atividade das enzimas desidrogenase e urease foram diretamente proporcionais ao aumento da idade das áreas. O C e N totais do solo, o N-NO3, o nitrogênio da biomassa microbiana (NBM), a atividade das enzimas desidrogenase e urease, bem como a macroporosidade correlacionaram-se positivamente e a microporosidade, negativamente, com o C e N da serapilheira. A partir da pRDA, o NBM e o carbono total do solo foram os atributos mais importantes para explicar o teor de N e C da serapilheira; a explicação compartilhada foi mais da metade de toda a explicação observada ou 28,2 %. A melhoria das condições físicas do solo e a adição de matéria orgânica que resultam na formação de uma serapilheira mais rica em N pode ser uma forma de melhorar as condições microbiológicas e químicas do solo e de acelerar o processo de recuperação.

Nucleation of diamond on silicon, SiAlON, and graphite substrates coated with an a-C:H layer

We investigated the influence of a hydrogenated disordered carbon (a-C:H) layer on the nucleation of diamond. Substrates c-Si<100>, SiAlON, and highly oriented pyrolytic graphite {0001} were used in this study. The substrate surfaces were characterized with Auger electron spectroscopy (AES) while diamond growth was followed with Raman spectroscopy and scanning electron microscopy (SEM). It was found that on silicon and SiAlON substrates the presence of the a-C:H layer enabled diamond to grow readily without any polishing treatment. Moreover, more continuous diamond films could be grown when the substrate was polished with diamond powder prior to the deposition of the a-C:H layer. This important result suggests that the nucleation of diamond occurs readily on disordered carbon surfaces, and that the formation of this type of layer is indeed one step in the diamond nucleation mechanism. Altogether, the data refute the argument that silicon defects play a direct role in the nucleation process. Auger spectra revealed that for short deposition times and untreated silicon surfaces, the deposited layer corresponds to an amorphous carbon layer. In these cases, the subsequent diamond nucleation was found to be limited. However, when the diamond nucleation density was found to be high; i.e., after lengthy deposits of a¿C:H or after diamond polishing, the Auger spectra suggested diamondlike carbon layers.

Continuous-time random-walk model for financial distributions

We apply the formalism of the continuous-time random walk to the study of financial data. The entire distribution of prices can be obtained once two auxiliary densities are known. These are the probability densities for the pausing time between successive jumps and the corresponding probability density for the magnitude of a jump. We have applied the formalism to data on the U.S. dollardeutsche mark future exchange, finding good agreement between theory and the observed data.

Continuous phase transition in a spin-glass model without time-reversal symmetry

We investigate the phase transition in a strongly disordered short-range three-spin interaction model characterized by the absence of time-reversal symmetry in the Hamiltonian. In the mean-field limit the model is well described by the Adam-Gibbs-DiMarzio scenario for the glass transition; however, in the short-range case this picture turns out to be modified. The model presents a finite temperature continuous phase transition characterized by a divergent spin-glass susceptibility and a negative specific-heat exponent. We expect the nature of the transition in this three-spin model to be the same as the transition in the Edwards-Anderson model in a magnetic field, with the advantage that the strong crossover effects present in the latter case are absent.

Non independent continuous-time random walks

The usual development of the continuous-time random walk (CTRW) assumes that jumps and time intervals are a two-dimensional set of independent and identically distributed random variables. In this paper, we address the theoretical setting of nonindependent CTRWs where consecutive jumps and/or time intervals are correlated. An exact solution to the problem is obtained for the special but relevant case in which the correlation solely depends on the signs of consecutive jumps. Even in this simple case, some interesting features arise, such as transitions from unimodal to bimodal distributions due to correlation. We also develop the necessary analytical techniques and approximations to handle more general situations that can appear in practice.

Parrondo-like behavior in continuous-time random walks with memory

The continuous-time random walk (CTRW) formalism can be adapted to encompass stochastic processes with memory. In this paper we will show how the random combination of two different unbiased CTRWs can give rise to a process with clear drift, if one of them is a CTRW with memory. If one identifies the other one as noise, the effect can be thought of as a kind of stochastic resonance. The ultimate origin of this phenomenon is the same as that of the Parrondo paradox in game theory.

The effect of continuous positive airway pressure on total cerebral blood flow in healthy awake volunteers.

PURPOSE: Continuous positive airway pressure (CPAP) is the gold standard treatment for obstructive sleep apnea. However, the physiologic impact of CPAP on cerebral blood flow (CBF) is not well established. Ultrasound can be used to estimate CBF, but there is no widespread accepted protocol. We studied the physiologic influence of CPAP on CBF using a method integrating arterial diameter and flow velocity (FV) measurements obtained for each vessel supplying blood to the brain. METHODS: FV and lumen diameter of the left and right internal carotid, vertebral, and middle cerebral arteries were measured using duplex Doppler ultrasound with and without CPAP at 15 cm H(2)O, applied in a random order. Transcutaneous carbon dioxide (PtcCO(2)), heart rate (HR), blood pressure (BP), and oxygen saturation were monitored. Results were compared with a theoretical prediction of CBF change based on the effect of partial pressure of carbon dioxide on CBF. RESULTS: Data were obtained from 23 healthy volunteers (mean&#8201;±&#8201;SD; 12 male, age 25.1&#8201;±&#8201;2.6 years, body mass index 21.8&#8201;±&#8201;2.0 kg/m(2)). The mean experimental and theoretical CBF decrease under CPAP was 12.5 % (p&#8201;<&#8201;0.001) and 11.9 % (p&#8201;<&#8201;0.001), respectively. The difference between experimental and theoretical CBF reduction was not statistically significant (3.84&#8201;±&#8201;79 ml/min, p&#8201;=&#8201;0.40). There was a significant reduction in PtcCO(2) with CPAP (p&#8201;=&#8201;<0.001) and a significant increase in mean BP (p&#8201;=&#8201;0.0017). No significant change was observed in SaO(2) (p&#8201;=&#8201;0.21) and HR (p&#8201;=&#8201;0.62). CONCLUSION: Duplex Doppler ultrasound measurements of arterial diameter and FV allow for a noninvasive bedside estimation of CBF. CPAP at 15 cm H(2)O significantly decreased CBF in healthy awake volunteers. This effect appeared to be mediated predominately through the hypocapnic vasoconstriction coinciding with PCO(2) level reduction. The results suggest that CPAP should be used cautiously in patients with unstable cerebral hemodynamics.