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In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m2. Consolidated knowledges are present only with the dose of 5 g/m2 in acute lymphoblastic leukemia. We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m2, to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m2 = 30 kg). The median age was 4.5 months (range 0–9). The median weight was 5.63 kg (range 3.12–9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 µM/L (range 227–790). The median systemic MTX clearance was 4.14 L/h/m2 (range 1.98–9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 µM/L (range 1.14–100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m2 can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion). Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg.

This paper examines ring size patterns of natural product macrocycles. Evidence is presented that natural macrocycles containing 14-, 16-, and 18-membered rings are of frequent occurrence based on a data mining study. The results raise a question about the limited diversity of macrocycle ring sizes and the nature of the constraints that may cause them. The data suggest that the preference bears no relationship to the odd-even frequency in natural fatty acids. The trends reported here, along with those reported previously (Wessjohann et al. (2005) Mol Divers 9:171), may be generalized to better understand the possible structure preferences of natural macrocycles.

We propose a mechanism that bilateral symmetry yields an entropic advantage for enzyme recognition. We suggest that bilateral symmetry may be a guiding principle used by nature to produce some particularly effective receptor–ligand interactions. An essential result is that bilateral symmetry is common among enzyme inhibitors, which coupled with an enhanced bond energy that connects dimer molecules compared to a reduced bond energy profile for higher oligomers provides a clue to explain the abundance of bilaterally symmetrical molecules found in Nature.

The application of Fourier analysis to study leaky waves has the advantage of simplicity, but it is not clear why the complex roots of the dispersion relations represent leaky waves, nor how the leakage occurs. We investigate the different kinds of leakage that can occur in a three layer plasma, and to which Fourier pseudomodes they are associated. We find four basic mechanisms, called “surface mode ...”, “single interface ...”, “trapped wave ...” and “lost insulation leakage”. These mechanisms appear in pure form only near certain limiting cases, in which the parameters of the problem take some special values. As soon as the parameters depart significantly from the limiting values, the behavior of the leaky wave complicates and mixtures of the mechanisms occur, in varying amounts. In consequence different points of the same complex branch of the spectrum may correspond to different mechanisms. All the complex branches of the spectrum correspond to leaky waves, but in general it is not possible to classify them according to type of leakage, except close to a limiting case. Since in a three layer configuration there are many of these, the spectrum of leaky waves is very complicated.

In a three layer compressible plasma we study MHD leaky waves described by Fourier modes of complex frequency. We follow a matrix method that yields four transcendental dispersion relations. The roots (real or complex) make up a spectrum of pseudomodes, consisting of a complicate set of infinite branches. We derive analytical properties that allow to study the topology of the spectrum, the conditions of existence of real and complex roots, the contacts and crossings of branches of different types, etc. Our results allow to analyze any particular case of interest.

We study numerically the Fourier pseudomodes of complex frequency, that represent leaky waves, for two configurations consisting of three layers of uniform plasma in equilibrium, using the methods developed in the previous papers. The spectra consist of an infinite set of branches. We introduce a shorthand notation that allows us to identify the branches and we discuss their behavior. We show examples of leaky waves that in the neighborhood of certain limiting cases correspond to some of the four basic mechanisms discussed in a previous paper.

The continuous infusion of glucose (1 mg/kg/min) via the carotid artery in anesthetized dogs produces a biphasic pattern of insulin secretion. The first peak reaches a maximum 3 min after glucose infusion and drops to basal level at 7 min. As long as the glucose infusion persists a slow and mantained increase in insulin level in the pancreaticoduodenal vein can be observed. The same amount of glucose infused in the general circulation via the jugular vein provoked a different pattern of insulin secretion. Cerebral glucose infusion to vagotomized dogs also produced a two phase response to insulin secretion, but the levels reached in the first phase were lower that those observed in the normal dogs. The infusion of glucose, via the jugular vein, in vagotomized dogs, failed to induce any change in plasma insulin levels. Our data suggest that a glucose load to the brain induces pancreatic insulin secretion mediated partially by the vagus nerves. These results are also compatible with the hypothesis that a humoral factor could be involved in the pancreatic response.

A new multiple sampling technique for obtaining blood from the portal vein has been used to investigate the effects of neurotensin on insulin and glucose portal blood levels in rats rendered hyperglycemic by a constant glucose infusion. The peptide has been first injected acutely (2 microgram/rat iv), and then constantly infused (0.5 microgram/min for 55 min). The preliminary results indicate that no effect of the acute injection could be observed, but hyperglycemia and hyperinsulinemia were induced by the constant infusion of the peptide. It is suggested that neurotensin may stimulate the release of insulin probably through a direct mechanism.