[Anaphylaxis to blue dyes]. / Anaphylaxie aux colorants bleus.

In medicine, vital blue dyes are mainly used for the evaluation of sentinel lymph nodes in oncologic surgery. Perioperative anaphylaxis to blue dyes is a rare but significant complication. Allergic reactions to blue dyes are supposedly IgE-mediated and mainly caused by triarylmethanes (patent blue and isosulfane blue) and less frequently by methylene blue. These substances usually do not feature on the anesthesia record and should not be omitted from the list of suspects having caused the perioperative reaction, in the same manner as latex and chlorhexidine. The diagnosis of hypersensitivity to vital blue dyes can be established by skin test. We illustrate this topic with three clinical cases.

[Management of adverse events induced by TNFalpha blocking agents]. / Allergologie: 1. Anti-TNFalpha: effets indésirables et implications pratiques.

TNFalpha blocking agents are effective and essential tools in the management of many inflammatory conditions including rheumatoid arthritis, spondylarthropathies and chronic inflammatory bowel disease. With time, some known side-effects have gained in importance and others have appeared. This article focuses on the potential risks of infection and autoimmunity induced by TNFalpha blocking agents and on the strategy to prevent and treat such adverse events.

[Cardiac involvement in connective tissue disease: the example of systemic lupus erythematosus]. / Atteintes cardiaques dans les connectivites: l'exemple du lupus érythémateux systémique.

When we think of cardiac affection in the context of systemic lupus erythematosus (SLE), we usually refer to pericarditis first. As frequent as this affection is, it is actually not the only cardio-vascular problem that occurs with this systemic inflammatory disease. Are the cardiac events--ranging from multiple heart valve involvements to increased cardiovascular risks--clinically significant? And are they involving a specific follow-up, treatment or support? We are therefore trying to evaluate these questions in order to give some recommendations to any practitioners following up a lupus patient, or a patient suffering from any other inflammatory systemic disease.

Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a common congenital malformation characterized by the absence of intramural ganglion cells of the hindgut. Recently, mutations of the RET tyrosine kinase receptor have been identified in 50 and 15-20% of familial and sporadic HSCR, respectively. These mutations include deletion, insertion, frameshift, nonsense, and missense mutations dispersed throughout the RET coding sequence. To investigate their effects on RET function, seven HSCR missense mutations were introduced into either a 1114-amino acid wild-type RET isoform (RET51) or a constitutively activated form of RET51 (RET-MEN 2A). Here, we report that one mutation affecting the extracytoplasmic cadherin domain (R231H) and two mutations located in the tyrosine kinase domain (K907E, E921K) impaired the biological activity of RET-MEN 2A when tested in Rat1 fibroblasts and pheochromocytoma PC12 cells. However, the mechanisms resulting in RET inactivation differed since the receptor bearing R231H extracellular mutation resulted in an absent RET protein at the cell surface while the E921K mutation located within the catalytic domain abolished its enzymatic activity. In contrast, three mutations mapping into the intracytoplasmic domain neither modified the transforming capacity of RET-MEN 2A nor stimulated the catalytic activity of RET in our ligand-independent system (S767R, P1039L, M1064T). Finally, the C609W HSCR mutation exerts a dual effect on RET since it leads to a decrease of the receptor at the cell surface and converted RET51 into a constitutively activated kinase due to the formation of disulfide-linked homodimers. Taken together, our data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.

Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation.

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (MEN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (MTC), a malignant tumor arising from calcitonin-secreting thyroid C cells, is the cardinal disease feature of this syndrome, and mortality in affected MEN-2 patients is mainly caused by this malignancy. Germ-line mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, are responsible for these three neoplastic-prone disorders. MEN2 mutations convert the RET protooncogene in a dominantly acting oncogene as a consequence of the ligand-independent activation of the tyrosine kinase. The majority of MEN2A and FMTC mutations are located in the extracellular domain and cause the replacement of one of five juxtamembrane cysteines by a different amino acid. To examine whether expression of a MEN2A allele of RET results in transformation of C cells, we have used the transgenic approach. Expression of the RET gene altered by a MEN2A mutation was targeted in C cells by placing the transgene under the control of the calcitonin gene-related peptide/calcitonin promoter. Animals of three independent transgenic mouse lines, which expressed the transgene in the thyroid, displayed overt bilateral C cell hyperplasia as early as 3 weeks of age and subsequently developed multifocal and bilateral MTC. Moreover, these tumors were morphologically and biologically similar to human MTC which afflicts MEN2 individuals. These findings provide evidence that the MEN2A mutant form of RET is oncogenic in parafollicular C cells and suggest that these transgenic mice should prove a valuable animal model for hereditary MTC.

Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations.

Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634-->Arg) and the unique MEN 2B mutation (Met918-->Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.

World-wide surveillance of influenza.

Influenza epidemics and pandemics resulting in excess mortality are due to various influenza viruses, in which through the accumulation of mutations the structure changes. A world-wide surveillance has been set up for early detection of new influenza virus strains and of epidemics or pandemics resulting thereof. Basing on such data the World Health Organisation (WHO) issues recommendations to Public Health authorities on the most efficient means for prevention.

Surveillance of influenza in Switzerland between 1987 and 1995.

During 8 years of continuous influenza surveillance in Switzerland (1987 to 1995), influenza A viruses predominated during 5 seasons and influenza B viruses during 3. The most severe outbreaks occurred in the 1988/89 season (A/H1N1 subtype), in the 1989/90 season (A/H3N2 subtype) and in the 1994/95 season (simultaneous outbreak of influenza A/H3N2 and B). From 1987 to 1993, peak activity of influenza A viruses was observed during December and January (for 8 weeks on average) while influenza B viruses were most active between February and March (ordinarily for 6 weeks). During the 1994/95 season, however, simultaneously increased activity of both influenza A/H3N2 and B viruses was observed, peaking at the end of March and lasting for about 9 weeks. The variants predominant in Switzerland largely corresponded antigenically to those isolated elsewhere in Europe, but a delay of one year was often observed. New strains detected at the end of a season (herald viruses) made it possible to forecast the type or subtype of virus which would predominate the next season. Isolation rates for A/H3N2 viruses were significantly higher in the 10-19 years and 60-plus age groups, whereas there was no statistical difference between age groups for A/H1N1 viruses. A decreasing isolation rate, corresponding to increasing age, was found for influenza B viruses. Increased mortality was observed in patients over 65 during the period of high influenza A/H3N2 activity, as was especially evident during the 1989/90 season.

Seroprevalence of rubella among women of childbearing age in Switzerland.

A seroepidemiological study was carried out in Switzerland to define the population susceptible to rubella among women of childbearing age. IgG antibodies to rubella virus were determined in 9,046 women giving birth between 1 August 1990 and 30 September 1991 in 23 of 26 Swiss cantons. These sera represented 10-20% of the yearly total number of births in each Swiss canton. Anti-rubella IgG was measured by an automated enzyme-linked fluorescent assay for use with a commercial system (Vidas Rub IgG, bio-Mérieux, France). Before the study population was screened, the commercial system was compared to the traditional hemagglutination-inhibition (HAI) test using 500 consecutive samples from parturient women. The sensitivity was 97.7%, the specificity was 100%, and agreement between the two tests was 97.8%. The discrepancies corresponded to very low titres of antibodies as measured by HAI. The seroprevalence of rubella nationwide in women of childbearing age in Switzerland was 94.3%. The seroprevalence was higher (96.5%) in the 5,677 women of Swiss nationality than in the 3,090 women of a different nationality (90.4%) (p < 0.001). In Swiss women the seroprevalence of rubella did not increase significantly with age and was identical in primiparous and in multiparous women, thus indicating that women of childbearing age are probably not sufficiently immunised.