Poincare Analyticity and the Complete Variational Equations

According to a theorem of Poincare, the solutions to differential equations are analytic functions of (and therefore have Taylor expansions in) the initial conditions and various parameters providing the right sides of the differential equations are analytic in the variables, the time, and the parameters. We describe how these Taylor expansions may be obtained, to any desired order, by integration of what we call the complete variational equations. As illustrated in a Duffing equation stroboscopic map example, these Taylor expansions, truncated at an appropriate order thereby providing polynomial approximations, can well reproduce the behavior (including infinite period doubling cascades and strange attractors) of the solutions of the underlying differential equations.Comment: 86 pages including 22 figure

Topotecan lacks third space sequestration

The objective of this study was to determine the influence of pleural and ascitic fluid on the pharmacokinetics of the antitumor camptothecin derivative topotecan. Four patients with histological proof of malignant solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several occasions in both the presence and absence of third space volumes. Serial plasma and pleural or ascitic fluid samples were collected during each dosing and analyzed by high-performance liquid chromatography for both the intact lactone form of topotecan and its ring-opened carboxylate form. The apparent topotecan clearance demonstrated substantial interpatient variability but remained unchanged within the same patient in the presence [110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven courses)]. Similarly, terminal half-lives and area under the concentration-time curve ratios of lactone:total drug in plasma were similar between courses within each patient. Topotecan penetration into pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range, 1.37-1.86 h), and ratios with plasma concentration increased with time after dosing in all patients. The mean ratio of third space topotecan total drug area under the concentration-time curve to that in plasma was 0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely administered to patients with pleural effusions or ascites and that there is substantial penetration of topotecan into these third spaces, which may prove beneficial for local antitumor effects

Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens

Anticancer drugs still are dosed based on the body-surface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r = 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens

The differential risk of oral contraceptives: the impact of full exposure history*

Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptive

Layered double hydroxides as nano additives in poly(ϵ-caprolactone)

Poly(e-caprolactone) MgAl - layered double hydroxides (MgAl-LDH) nanocomposites were prepared by melt intercalation. Two organically modified MgAl-LDH, stearic acid (stearate) and sodium dodecyl sulphate (SDS), were used. Nanocomposites morphology was studied by XRD and TEM. Thermal properties were analysed by TG and DSC. Although both systems showed presence of a mixed morphology, exfoliated and intercalated, MgAl-LDH stearate nanocomposites showed a better dispersion of inorganic platelets. TEM images showed the presence of individual platelets in the PCL matrix. MgAl-LDH SDS nanocompositeshttp://www.tandfonline.com/loi/gmcl2

Titania recovery from low-grade titanoferrous minerals

In this study a novel process for extraction of titanium valuables from its minerals is presented. The process entails roasting of titanium ore with alkaline metal salt, hydrolysing fused cake and dissolution in acid. Optimum conditions were found to be 1 h fusion at 850 °C, using 2:1 mole ratio, NaOH:FeTiO4, irrespective of the particle size interval used in this work. It was found that under these conditions ≈80% of titanium was recovered. Na0.75Fe0.75Ti0.25O2, NaFeTiO4 and Na2Fe2Ti3O10 were the dominant phases at this temperature. The presence of these phases is viewed as beneficial to the economics of the process, it consumes less NaOH. Fusions conducted at 550 °C or below produced chiefly binary phases, Na2TiO3 and NaFeO4, reducing process economy. Optimum leaching conditions were S/L=0.26, leaching at 75 °C, for 15 min. 85% of NaOH was recovered, under these conditions. Leaching obeys shrinking core mechanism model.The University Eduardo Mondlane, Mozambique, the THRIP program of the Department of Trade and Industry, the National Research Foundation of South Africa as well as Xyris Technology CC.http://www.elsevier.com/locate/hydrome

Microwave conductivity of a d-wave superconductor disordered by extended impurities: a real-space renormalization group approach

Using a real-space renormalization group (RSRG) technique, we compute the microwave conductivity of a d-wave superconductor disordered by extended impurities. To do this, we invoke a semiclassical approximation which naturally accesses the Andreev bound states localized near each impurity. Tunneling corrections (which are captured using the RSRG) lead to a delocalization of these quasiparticles and an associated contribution to the microwave conductivity.Comment: 8 pages, 4 figures. 2 figures added to previous versio

Modelling of strain effects in manganite films

Thickness dependence and strain effects in films of $La_{1-x}A_xMnO_3$ perovskites are analyzed in the colossal magnetoresistance regime. The calculations are based on a generalization of a variational approach previously proposed for the study of manganite bulk. It is found that a reduction in the thickness of the film causes a decrease of critical temperature and magnetization, and an increase of resistivity at low temperatures. The strain is introduced through the modifications of in-plane and out-of-plane electron hopping amplitudes due to substrate-induced distortions of the film unit cell. The strain effects on the transition temperature and transport properties are in good agreement with experimental data only if the dependence of the hopping matrix elements on the $Mn-O-Mn$ bond angle is properly taken into account. Finally variations of the electron-phonon coupling linked to the presence of strain turn out important in influencing the balance of coexisting phases in the filmComment: 7 figures. To be published on Physical Review

Plasmodium falciparum translational machinery condones polyadenosine repeats

Plasmodium falciparum is a causative agent of human malaria. Sixty percent of mRNAs from its extremely AT-rich (81%) genome harbor long polyadenosine (polyA) runs within their ORFs, distinguishing the parasite from its hosts and other sequenced organisms. Recent studies indicate polyA runs cause ribosome stalling and frameshifting, triggering mRNA surveillance pathways and attenuating protein synthesis. Here, we show that P. falciparum is an exception to this rule. We demonstrate that both endogenous genes and reporter sequences containing long polyA runs are efficiently and accurately translated in P. falciparum cells. We show that polyA runs do not elicit any response from No Go Decay (NGD) or result in the production of frameshifted proteins. This is in stark contrast to what we observe in human cells or T. thermophila, an organism with similar AT-content. Finally, using stalling reporters we show that Plasmodium cells evolved not to have a fully functional NGD pathway

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios