Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Sexual Developmental Disorders in Pediatrics.

Abstract: Disorders of sex development (DSD) are a heterogeneous group of pathologies that result in an alteration in sex determination or differentiation. DSD are estimated to affect 1: 4,500 newborns and according to the 2006 Chicago Consensus classification, DSD can be divided into three categories: those with a 46 XX karyotype, those with a 46 XY karyotype and those relating to sex chromosomes. It is crucial to correctly identify the pathology already in the first days of life to direct the patient and his family to the best path of care. For this reason, the role of the pediatrician is fundamental in the correct identification of the clinical picture and in supporting the family during the long process that involves the management of these patients. To make a diagnosis, it is necessary to follow a path led by a multidisciplinary team that includes several steps such as the execution of the genetic analysis, the evaluation with diagnostic imaging methods and laboratory evaluations. The therapeutic management, on the other hand, is still very complex even if in recent years we have moved from an attitude of early gender reassignment to an approach of watchful waiting to let the patient choose when she/he is mature enough to do so, which gender she/he feels to belong. It should not be forgotten that throughout this process the pediatrician must be both supportive and clinically active in the management of the child and his family.

In situ visualization of o-phthalate esters in gastrointestinal tract of the frog Rana esculenta.

The regional distribution and relative occurrence of phthalates were studied immunohistochemically by confocal laser scanning microscopy in the alimentary tract of the green frog, Rana esculenta, using an antibody against o-phthalate esters. Many positive sites indicating the basal presence of phthalate esters were identified. The immunoreactive cells were located in the gastric glands of the stomach and in the intestinal epithelium regions with variable frequencies. The regional distribution of phathalate-accumulating cells resembled that of fish and demonstrated that these endocrine disruptors not only enter via the alimentary canal, but also bioaccumulate inside cells specialized in secretion as well as absorption functions.

Effects of phthalate esters on actin cytoskeleton of Py1a rat osteoblasts.

We evaluated, by confocal laser scanning microscopy, the actin cytoskeleton of immortalized rat Py1a osteoblasts treated with phthalate esters (butyl benzyl phthalate, BBP and dibutyl phthalate, DBP), endocrine disruptors with estrogenic activity. We observed some peculiar modifications of actin cytoskeleton and cells changing from a spindle shape to a rounded form. In particular, F-actin formed thick bundles around the cell membrane but only a weak labeling was observed in rounded cells. Also influence on apoptosis and short-term effects on FGF-2 were studied. It was found that BBP and DBP exert their action in a similar way, act in a transient manner and do not induce apoptosis.

Phthalate esters influence FGF-2 translocation in Py1a rat osteoblasts.

Exposure of the Py1a rat osteoblastic cells to butyl benzyl phthalate (BBP) and dibutyl phthalate (DBP) showed that these endocrine disrupting chemicals (EDC) strongly and reversibly affect the cytoplasmic fibroblast growth factor-2 (FGF-2) translocation into the nucleus in a dose-dependent and time-related manner. Stimulation of cells with high concentrations of BBP or DBP for short timing gave results comparable to those of cells treated with low concentrations for long timing. By confocal laser scanning microscope (CLSM) analysis it was found that the first relevant effect resulted in an accumulation of FGF-2 near the nuclear envelope, sometimes in the shape of clusters; the growth factor was then translocated into the nucleus and, finally, after long periods of exposure, the basal nuclear and cytoplasmic binding, typical of unstimulated cells, was re-established. In addition it was found that phthalate esters did not affect the FGF receptor 2 (FGFR-2) but decreased Con A binding indicating a possible inhibition of collagen fiber assembly. The different concentrations and timing of exposure of BBP and DBP affected the FGF-2 modulation in a similar way. Noticeable cumulative effects of BBP and DBP were not observed.

Resultados preliminares de 7 provincias argentinas en el marco de una propuesta de Evaluación Nacional de la Inteligencia Sensoriomotriz a bebes de 6 a 30 meses / Preliminary results from 7 provinces of argentina within a proposition of a National Assessment of Sensory Motor Intelligence for argentinean babies of 6 to 30 months old

El objetivo es presentar los resultados preliminares de siete provincias argentinas correspondientes a una investigación que se enmarca en un proyecto UBACyT 2008-2010, cuyo título es "Evaluación Nacional de la Inteligencia Sensoriomotriz a bebés de 6 a 30 meses". El objetivo principal de dicha investigación es conocer las etapas del proceso de construcción de la inteligencia práctica en bebés argentinos en las distintas provincias de la Argentina y la elaboración de baremos a nivel nacional y por cada provincia, administrando la Escala Argentina de Inteligencia Sensoriomotriz (EAIS). La muestra se encuentra compuesta por 109 niños de las provincias de Santa Fe, Santa Cruz, Río Negro, Entre Ríos, Salta, Córdoba y Buenos Aires. En el análisis de los datos, se observó que el 67% de los niños evaluados obtuvieron resultados normales, 16.5% de riesgo y 3.7% de retraso. Es decir, el 20% de los niños evaluados obtuvieron resultados de riesgo y retraso

The aim of this article is to present the preliminary results from seven provinces of Argentina within an investigation belonging to UBACyT 2008-2010, which title is "National assessment of the sensorymotor intelligence in babies of 6 to 30 months old". The main objective of the research is to assess the periods involved in the construction process of the practical intelligence in Argentinean babies from different provinces, as well as the elaboration of national and provincial percentiles, administrating the Argentinean scale of Sensorymotor intelligence (EAIS). The sample is composed by 109 babies from the Argentinean provinces of Santa Fe, Salta Cruz, Río Negro, Entre Ríos, Salta, Córdoba y Buenos Aires. In the analysis of the data, it was observed that 67% of the babies obtained normal results, 16.5% obtained results indicating risk and 3.7% delayed. In other words, 20% of the assessed babies obtained results indicating risk and delayed in the sensorymotor intelligence

[Erotic temperance: fortune and development of an Epicurean suggestion in the imperial Roman age]. / La temperanza erotica: una raccomandazione Epicurea riproposta e idealizzata en eta imperiale.

The purpose of this writing is to follow the course of an idea, namely that of erotic temperance, which the Epicureans most proably derived as a corollary of their originary ethics. It was during the imperial Roman age that such an idea met a certain audience for different reasons, two of which at least cannot remain unnoticed. The first reason was the theoretical and clinic support given to this idea by such Epicurean oriented physicians as Rufus and Soranus, and by Areteus; the other one should have been the meeting of the notion of erotic temperance with such ethical principles as the moderation, the control of the passions, the impassibility of man towards life events, and a new vision the relationship between husband and wife, which entered into the pattern of the gentlemen's behaviour during the imperial age contributing to the starting of a new ethics. But, if erotic temperance represented on the one hand an ideal for the cultivated class of Roman imperial society, it was on the other perceived as a scrupulously observed realty by Germans, and as one of the principal reasons of their physical and mortal energy. Furthermore, the ideal of a severe erotic control of the early Christians offer precise evidence, will represent an important ground of agreement for theirs and contemporary pagan ethics.

Sialic acid derivatives and their distribution in rat sublingual gland acini during pre- and post-natal development.

Sialoglycoconjugates in rat sublingual gland acinar cells, at different stages of pre- and post-natal development, were investigated in situ with specific lectins and by the selective removal of terminal sialic acids. Cleavage of acetyl substituents sited in the pyranose ring and/or polyhydroxyl side chain was used as an additional means of characterising the glycoconjugates. The first expression of terminal sialic acid linked to beta-galactose was found at gestational day 17 and progressive different derivatives were observed. The terminal disaccharide sialic acid-N-acetylgalactosamine was constantly visualized in the sublingual gland from gestational day 18. In both terminal disaccharides, sialic acids were characterized by variable degrees of acetylation and were found to be highly packaged and responsible for the hydration coat. The complex data obtained indicated that the sublingual gland is characterized by a marked fluctuation of complex sialoglycoconjugates that differ from those in the submandibular gland of the same species.