Assessment of Labrasol/Labrafil/Transcutol (4/4/2, v/v/v) as a non-clinical vehicle for poorly water-soluble compounds after 4-week oral toxicity study in Wistar rats.

Drug safety research is frequently faced with the challenge of the selection of appropriate vehicles for use in in vivo non-clinical safety assessment studies. Reported here are the results of blend Labrasol, Labrafil and Transcutol, [L/L/T, (4/4/2, v/v/v)], excipients used as bioavailability enhancer and solubilizer for poorly water-soluble compounds and tested daily for 4 weeks by oral route in Wistar rats (10/sex/group) at dose volumes of 5, 10 or 20 mL/kg/day and compared to controls given 20 mL/kg/day of 1% (w/v) hydroxyethylcellulose in purified water. L/L/T was broadly well tolerated at 5 mL/kg/day and lethal at 20 mL/kg/day in 1 of 20 rats treated at this level. Changes in appearance and behaviour were observed from 10 mL/kg/day with volume-related incidence, severity and duration. Reduced feed intake observed from 5 (females) or 10 mL/kg/day (males) resulted in low bodyweights for high volume males only (-11% of controls). There was a volume-related induction of hepatic CYP 1A1/2, 2B1/2 and/or 2E1 subfamilies from 5 mL/kg/day, with high liver weight, centrilobular hepatocellular hypertrophy and high ALT, triglyceride and cholesterol serum values at 20 mL/kg/day. Renal tubular dilation in medulla, cortical cell degeneration/necrosis with granular material in adjacent glomerular spaces, crystal deposits in the inner medulla, papilla and/or renal pelvis, and tubular mineralization, associated with proteinuria and calcium oxalate crystalluria, were observed at 20 mL/kg/day as well as vacuolation in the adrenal cortex, with a sex-dependant localization. According to these results, 5 mL/kg/day was considered as an acceptable volume for further use of L/L/T (4/4/2, v/v/v) blend as a vehicle for poorly water soluble drugs in Wistar rat toxicity studies.

Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas.

Chromosomal translocations joining the immunoglobulin (IG) and MYC genes have been extensively reported in Burkitt's and non-Burkitt's lymphomas but data concerning MYC rearrangements with non-IG partners are scarce. In this study, 8q24 breakpoints from 17 B-cell lymphomas involving non-IG loci were mapped by fluorescence in situ hybridization (FISH). In seven cases the breakpoint was inside a small region encompassing MYC: in one t(7;8)(p12;q24) and two t(3;8)(q27;q24), it was telomeric to MYC whereas in four cases, one t(2;8)(p15;q24) and three t(8;9)(q24;p13) it was located in a 85 kb region encompassing MYC. In these seven cases, partner regions identified by FISH contained genes known to be involved in lymphomagenesis, namely BCL6, BCL11A, PAX5 and IKAROS. Breakpoints were cloned in two t(8;9)(q24;p13), 2.5 and 7 kb downstream from MYC and several hundred kb 5' to PAX5 on chromosome 9, joining MYC to ZCCHC7 and to ZBTB5 exon 2, two genes encoding zinc-finger proteins. In these seven cases, MYC expression measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) was significantly higher when compared to that of patients without 8q24 rearrangement (P=0.006). These results suggest that these rearrangements are the consequence of a non-random process targeting MYC together with non-IG genes involved in lymphocyte differentiation and lymphoma progression.

Two patterns of chromosomal breakpoint locations on the immunoglobulin heavy-chain locus in B-cell lymphomas with t(3;14)(q27;q32): relevance to histology.

The t(3;14)(q27;q32) is the most common translocation involving BCL6 in B-cell lymphoma. Although this translocation was predominantly associated with diffuse large B-cell lymphoma (DLBCL), recent studies have shown that it can also be found in follicular lymphomas (FL), often associated with a large cell component. To further investigate the relationship that might exist between this translocation and the phenotype of the tumors, we studied 34 lymphomas with a t(3;14)(q27;q32). Twenty cases were DLBCL, 14 FL and most cases, regardless of histology, were negative for the expression of CD10 (26/32, 81%). We identified the IGH switch region involved in the translocation for 32 cases. Our data indicate that in DLBCL most breakpoints involve the switch mu (17/19; 89%), whereas in FL most involve a switch gamma (9/13; 70%) (P=0.0016, Fisher's exact test). This correlation between the histology and the structure of the translocated allele suggests that the lymphomas with Smu and Sgamma translocations may originate from different cells, or that the substituted regulatory regions that come to deregulate BCL6 may affect the presentation of the disease.

Effect of dietary lipid (soybean lecithin and triacylglycerol) on hepatic F-actin microfilaments in cyclosporine A-treated rats: image analysis by confocal laser scanning microscopy.

We studied and quantified the effect of cyclosporine A on hepatic F-actin on bile canalicular and basolateral membranes in rats fed either soybean lecithin, triacylglycerol-enriched diet, or low-fat diet by means of confocal laser scanning microscopy imaging. The phalloidin-FITC staining of F-actin was quite normal in the lecithin-cyclosporine A group but decreased significantly in the other cyclosporine A-treated groups (by 40% and 25% of control in triacylglycerol-cyclosporine A and cyclosporine A groups, respectively). The alteration of F-actin by cyclosporine A, related to cholestasis evidenced by a decrease in bile salt secretion, was prevented by dietary soybean lecithin and amplified by dietary soybean triacylglycerol.

Effect of dietary lipids on hepatic Na+,K(+)-ATPase in cyclosporine A-treated rats: immunocytochemical analysis of alpha1 subunit by confocal laser scanning microscopy imaging.

We studied the effect of dietary soybean lecithin or triacylglycerol on hepatic Na+,K(+)-ATPase in cyclosporine A-treated rats by means of quantitative immunocytochemistry. Cyclosporine A-treated rats were fed lecithin or a triacylglycerol-enriched diet or a low-fat diet. As a control, one group was only fed the low-fat diet; the three other groups were treated with cyclosporine A solvent and received the low fat, lecithin, or triacylglycerol diet. Bile canalicular staining significantly decreased in all cyclosporine A-treated groups with the higher values in lecithin-fed rats. In basolateral membranes, no decrease was observed in the lecithin-cyclosporine group, in contrast to the other groups. The triacylglycerol-cyclosporine group had lower values in both membrane domains. The alteration of Na+,K(+)-ATPase by cyclosporine A was related to cholestasis evidenced by a decrease in bile salt secretion. These modifications were prevented by dietary soybean lecithin and amplified by dietary soybean triacylglycerol.

Modification of Ca2+, Mg2+-ATPase and F-actin distribution in hepatocytes of cyclosporine A treated rats. Effect of soyabean lecithin and triacylglycerol.

We studied the effect of cyclosporine A on hepatic Ca2+, Mg2+-ATPase and F-actin on bile canalicular and basolateral membranes in rats fed either soyabean lecithin, or triacylglycerol enriched diet, or low fat diet. Ca2+, Mg2+-ATPase histochemical activity was not modified in lecithin-cyclosporine A group, whereas the activity was decreased in the other groups. The triacylglycerol-cyclosporine A group had the lower activity. The histochemical staining of F-actin was quite normal in lecithin-cyclosporine group but decreased in the other cyclosporine A treated groups. The lower staining was observed in the triacylglycerol-cyclosporine group. The alteration of Ca2+, Mg2+-ATPase and F-actin by cyclosporine A, related to cholestasis evidenced by a decrease in bile salt secretion, were prevented by dietary soyabean lecithin and amplified by dietary soyabean triacylglycerol.

[Analysis of professional applications of training given to general nursing care staff in continuing education]. / Analyse des applications sur le terrain professionnel de l'enseignement dispensé à des infirmières en soins généraux dans le cadre de la formation continue.

At a time when any leaders, either political or socioeconomical speak about "productivity, professional qualification, high-technology, research, etc.", it seemed to us that it was essential, as far as Public Health is concerned, to analyse through a medium-sized hospital the vocational training given to nurses working in general care. What does the nursing staff think about it? What about the "educational quality"? What are the consequences and effects of this training on a professional and human ground? Our hypothesis of research is to invalidate or to confirm those elements (different from those found in literature) can be more helpful to put into pratice the training on a professional ground. Those elements are: a number of training attended by nurses (from 6 to 12 in 5 years) ans which take the educational principles into account, that is why we have decided to condiser what presently exist, that is to say: the hospital and its plan, the current training, the nursing staff concerned and alle the possible means to succeed. Like this the problem was formulated and we could search a review for elements which sustain our analysis. The results of our research, which was based on a methodological way, prove that there is not only a great variety of applications of those teachings on a professional ground but also no application of the teachings on a professional ground. From this study and apart from the educational quality, we can note that the training subjects must be in connection with the hospital development, society and the medical profession. Anyway, the trainings are short, theoretical, do not fit in with the professional ground and do no consider the knowledge people acquired from other trainings. Our conclusion tend to confirme that the vocational training is necessary as well as its application from which the nursing staff can gain a lot.

[Necrolytic migrating erythema without glucagonoma]. / Erytheme necrolytique migrateur sans glucagonome.

INTRODUCTION: The glucagonoma syndrome is an uncommon but well-known entity associating erythema necroticans migrans (ENM) with glucagonoma. CASE REPORT: A 43-year-old man with a past history of alcoholic cirrhosis and ascitis was hospitalized for skin disorders which had developed over the past 4 months. Centrifugal erythematous skin lesions were observed, some with non-turgid bullae and marginal desquamation, others with an erosive center. Lesions first appeared on the hands then diffused widely without involving the periorifical areas, folds and lower limbs. Laboratory results revealed an anemia, hypovitaminosis K, cholestatic liver failure, a beta-gamma block and low zinc levels. Histology study of the skin biopsy demonstrated a << Neapolitan trench >> image suggestive of ENM. A paraneoplasic syndrome and pancreas tumor were not found. Despite supplementation with zinc, amino acids and vitamins, the patient died from his liver disease. DISCUSSION: There have been 4 cases of ENM reported in the literature, all in cirrhosis patients, two of which had low zinc levels. Our case is thus the third with cirrhosis and low zinc. Bazex's syndrome, acrodermatitis enteropathica, annular chronic lupus erythematosis and annular superficial pemphigus were eliminated as possible diagnoses. The failure of zinc and amino acid supplementation would favor the secondary nature of the zinc deficiency and the predominant role of cirrhosis in this skin disease. The possible role of essential fatty acids in ENM is raised.