A recycling framework for the construction of Bonferroni‐based multiple tests

In this paper we describe Bonferroni‐based multiple testing procedures (MTPs) as strategies to split and recycle test mass. Here, ‘test mass’ refers to (parts of) the nominal level α at which the family‐wise error rate is controlled. Briefly, test mass is split between different null hypotheses, and whenever a null hypothesis is rejected, the part of α allocated to it may be recycled to the testing of other hypotheses. These recycling MTPs are closed testing procedures based on raw p‐values associated with testing the individual null hypotheses, and the class of such MTPs includes, for example, serial and parallel gatekeeping, fallback and Holm procedures. Graphical displays and a concise algebraic notation are provided for such MTPs. This recycling approach has pedagogical advantages and may facilitate the tailoring of MTPs for different purposes. Copyright © 2009 John Wiley & Sons, Ltd.     

Accumulation of toxic metals (Pb and Cd) in the sea urchin Diadema aff. antillarum Philippi, 1845, in an oceanic island (Tenerife,Canary Islands)

This document shows the results obtained from a study on the concentration of toxic heavy metals in the internal tissue and exoskeleton of sea urchins, collected from their natural habitat. The levels of lead and cadmium were measured by Graphite Furnace Atomic Absorption Spectrometry. The mean concentrations of lead and cadmium in the internal tissue were 304.04 and 260.54 μg/kg respectively, whereas in the shell they were 185.02 and 142.48 μg/kg. We also performed a statistical analysis of the differences in the distribution of metals between their exoskeleton and their internal content, a correlation study of the metal content in internal tissue and shell and sampling areas, and a correlation study between the metal content and sample size. Since the sea urchin Diadema antillarum presents a wide range of variation in metal content, this study suggests that this species is an excellent bioindicator of heavy metal contamination. © 2009 Wiley Periodicals, Inc. Environ Toxicol, 2010.     

Reorganization of cytoplasm in the zebrafish oocyte and egg during early steps of ooplasmic segregation.

The aim of this work is to determine when and how ooplasmic segregation is initiated in the zebrafish egg. To this end, the organization of the ooplasm and vitelloplasm were examined in oocytes and eggs shortly after activation. Ooplasmic segregation, initiated in the stage V oocyte, led to the formation of ooplasmic domains rich in organelles, and ribonucleoproteins. A linear array of closely arranged peripheral yolk globules separated an outer domain of ectoplasm from an inner domain of interconnected endoplasmic lacunae. The structure of this yolk array and the distribution of microinjected labeled tracers suggests that it may provide a barrier limiting ooplasm transit. Loosely arranged yolk globules at the animal hemisphere allow wide connections between the endoplasm and a preblastodisc domain. Activation caused further segregation of ooplasm, reorganization of endoplasmic lacunae, and blastodisc growth. The presence of an endoplasmic cytoskeleton suggests that these changes may be driven by microtubules and microfilaments.     

Molecular modeling and metabolic studies of the interaction of catechol-O-methyltransferase and a new nitrocatechol inhibitor.

Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a central role in the metabolic inactivation of neurotransmitters and neuroactive xenobiotics possessing a catechol motif. 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone (BIA 3-202) is a novel nitrocatechol-type inhibitor of COMT, the potential clinical benefit of which is currently being evaluated in the treatment of Parkinson's disease. In the present work we characterize the molecular interactions of BIA 3-202 within the active site of COMT and discuss their implication on the regioselectivity of metabolic O-methylation. Unrestrained flexible-docking simulations suggest that the solution structure of this complex is better described as an ensemble of alternative binding modes, in contrast to the well defined bound configuration revealed by the X-ray structures of related nitrocatechol inhibitors, co-crystallized with COMT. The docking results wherein presented are well supported by experimental evidence, where the pattern of in vitro enzymatic O-methylation and O-demethylation reactions are analyzed. We propose a plausible explanation for the paradoxical in vivo regioselectivity of O-methylation of BIA 3-202, as well as of its related COMT inhibitor tolcapone. Both compounds undergo in vivo O-methylation by COMT at either meta or para catechol hydroxyl groups. However, results herein presented suggest that, in a subsequent step, the p-O-methyl derivatives are selectively demethylated by a microsomal enzyme system. The overall balance is the accumulation of the m-O-methylated metabolites over the para-regioisomers. The implications for the general recognition of nitrocatechol-type inhibitors by COMT and the regioselectivity of their metabolic O-methylation are discussed.     

Lack of developmental toxicity of D-003: a mixture of long-chain fatty acids in rats.

D-003 is a mixture of long-chain fatty acids isolated and purified from sugar cane wax, the major component of which is 1-octacosanoic acid and which possesses effective antiplatelet, antithrombotic and cholesterol-lowering effects. D-003 was suspended in 1% acacia gum solution, and given daily by gavage to rats at dose levels of 5, 100 and 1000 mg/kg/day on days 6 through 15 of gestation. Cyclophosphamide, serving as a positive control, was given at the dose of 50 mg/kg/day on day 15 of gestation. Evidence of maternal or developmental toxicity was not observed in the groups treated with D-003. Maternal clinical signs of toxicity were not observed and the analysis of initial body weight and the body weight gain during the treatment period was comparable among the groups treated with D-003 and control. As expected, cyclophosphamide caused both embryotoxic and teratogenic effects in rats. Meanwhile, no adverse effects on reproductive performance, or on embryonic or fetal development, including visceral and skeletal examination, were seen in any of the groups administered D-003. It is concluded that D-003 administered up to 1000 mg/kg/day did not induce any evidence of developmental toxicity.     

Scale-up of Adhesive Transdermal Drug Delivery Systems

Pharmaceutical Research -     

Primary spinal intramedullary malignant lymphoma. A case report

A rare case of primary malignant intramedullary lymphoma, localized in the cervical part of the spinal cord, is presented. The onset of clinical symptoms was associated with herpes zoster infection. Surgery led to the histological diagnosis. The clinical investigations excluded the presence of lymphoma in other sites in the central nervous system and in the extraneural organs. Postoperative irradiation and chemotherapy effected relict of neurological symptoms.