Thioredoxin reductase 1 is upregulated in atherosclerotic plaques: specific induction of the promoter in human macrophages by oxidized low-density lipoproteins.

Uptake of modified low-density lipoproteins (LDLs) by macrophages in the arterial wall is an important event in atherogenesis. Indeed, oxidatively modified LDLs (oxLDLs) are known to affect various cellular processes by modulating oxidation-sensitive signaling pathways. Here we found that the ubiquitous 55 kDa selenoprotein thioredoxin reductase 1 (TrxR1), which is a key enzyme for cellular redox control and antioxidant defense, was upregulated in human atherosclerotic plaques and expressed in foam cells. Using reverse transcription polymerase chain reaction analysis, we also found that oxLDLs, but not native LDLs (nLDLs), dose-dependently increased TrxR1 mRNA in human monocyte-derived macrophages (HMDMs). This stimulating effect was specific for oxLDLs, as pro-inflammatory factors, such as lipopolysaccharides (LPSs), interleukin-1beta (IL-1beta), interleukin-6 (Il-6), and tumor necrosis factor alpha (TNFalpha), under the same conditions, failed to induce TrxR1 mRNA levels to the same extent. Moreover, phorbol ester-differentiated THP-1 cells or HMDMs transiently transfected with TrxR1 promoter fragments linked to a luciferase reporter gene allowed identification of a defined promoter region as specifically responding to the phospholipid component of oxLDLs (p <.05 vs. phospholipid component of nLDLs). Gel mobility shift analyses identified a short 40-nucleotide stretch of the promoter carrying AP-1 and HoxA5 consensus motifs that responded with an altered shift pattern in THP-1 cells treated with oxLDLs, however, without evident involvement of either the Fos, Jun, Nrf2 or HoxA5 transcription factors.

[Expression of cytokines and their receptors in left ventricular hypertrophy in TGR(mRen2)27 rats]. / Expression des cytokines et de leurs récepteurs dans le ventricule gauche hypertrophique du rat TGR(mRen2)27.

Variations in the expression of cytokines from the interleukin-6 (IL-6) family: ciliary neurotrophic factor (CNTF), leukaemia inhibitory factor (LIF), and cardiotrophin 1 (CT-1) were studied during cardiac remodelling leading to left ventricular hypertrophy (LVH) in TGR(mRen2)27 rats at the age of 8 and 20 weeks. The cytokines mRNA levels within the free wall of the left ventricle were measured by semi-quantitative RT-PCR standardised with 18S. They were compared between heterozygous rats for the mRen2 transgene (TG+/-) and control rats (TG-/-). No significant difference was observed between results obtained at 8 and 20 weeks of age. At 20 weeks of age, TGR(mRen2)27 rats showed higher levels of mRNA LIF and IL-6 respectively by 52 and 55% compared to the control rats [LIF TG+/-: 3.17 +/- 0.21, TG-/-: 2.09 +/- 0.03; p < 0.001; n = 5; and IL-6 TG+/-: 1.53 +/- 0.13; TG-/-: 0.99 +/- 0.17; p < 0.05; n = 5]. By contrast, no variation of mRNAs levels of CT-1 and gp 130 genes was observed between control and transgenic rats. Concerning the cytokine receptors, the levels of mRNA for IL-6R did not vary while those of receptor subunits LIFR and CNTFR were decreased respectively by 48 and 42% in transgenic rats vs controls [LIFR TG+/-: 0.48 +/- 0.01; TG-/-: 0.92 +/- 0.08 p < 0.001; n = 5; and CNTFR TG+/-: 1.07 +/- 0.08; TG-/-: 1.85 +/- 0.18; p < 0.01; n = 5]. Therefore, these results show a specific pattern of activation of the cytokines pathway in the LVH of the TGR(mRen2)27 rat.

[Cardiotoxicity of 5-fluorouracil: report of 6 cases]. / Cardiotoxicité du 5-fluorouracil: à propos de 6 nouveaux cas.

5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite, is widely used in the treatment of cancers of the digestive tract and breast. The clinical cardiotoxicity of 5-FU was first reported in 1975. Adverse cardiac effects include coronary disorders, heart failure and sudden death of suspected cardiac origin. Six new cases are reported, including 5 cases of angina and one of heart failure. The patients, 4 males and 2 females, were 26 to 71 years of age (mean: 56.2). They had no medical history of heart failure, myocardial ischemia or electrocardiographic anomalies prior to 5-FU treatment. Three patients had hypertension of whom one had had type-II diabetes mellitus for the past 20 years. Clinical symptoms included chest pain in 4 patients and heart failure in one, whereas the last patient had ECG changes with no associated clinical symptoms. Clinical symptoms of angina totally disappeared after the cessation of 5-FU administration, but heart failure was alleviated only after the introduction of digitalis, a converting-enzyme inhibitor and a diuretic. It has been estimated that 1.6% of patients treated with 5-FU develop adverse cardiac effects. Patients at greater risk are those with a history of ischemic cardiac disease, thoracic radiotherapy or high-dose 5-FU therapy. The mechanism involved is not clearly elucidated. Spasms of the coronary arteries or toxic inflammation of the myocardium have been suspected. These 6 new cases confirm the potential for cardiotoxicity of 5-FU and the need for careful cardiac monitoring of treated patients.

Spindle cell lipoma of the scalp: a case report and review.

Cutaneous surgeons frequently evaluate and manage soft tissue tumors arising on the head and neck of adults. Of these, the most common tumor is the lipoma, and specific mesenchymal variants of lipoma occur classically on the head and neck. We describe a case of a large spindle cell lipoma of the posterior scalp, in order to highlight the classic location and differential diagnosis of the lipoma variants presenting commonly in this anatomic region. In addition, we review the role of preoperative imaging studies of scalp soft tissue tumors and discuss how imaging may assist the dermatologic surgeon in establishing the diagnosis and designing a rational surgical approach.

The spread and uptake pattern of intracerebrally administered oligonucleotides in nerve and glial cell populations of the rat brain.

The fate of 15-mer phosphorothioate-modified antisense oligonucleotides to c-fos was followed after their microinjection into rat brain. Using radiolabeled oligonucleotides, it was demonstrated that the bulk of the material stays in the injected region but that a minor part is transported with the projection pathways to regions far away from the site of injection. Using tetramethylrhodamine-isothiocyanate (TRITC) labeling as well as fluorescein isothiocyanate (FITC) labeling, it was found that the oligonucleotides were taken up by a great number of cells within 30 minutes after the injection. A diffuse cytoplasmic staining and also nuclear staining were observed in these cells, which could be identified exclusively as neurons by double labeling for the neuron-specific protein NeuN. At later times (6, 24, and 48 hours), the appearance of the oligonucleotides changed gradually to a punctate cytoplasmic staining, which by electron microscopic analysis was shown to be caused by the presence of the oligonucleotides in intracellular vesicles. The pattern of intracellular fluorescence was changed when the oligonucleotides were injected together with the cationic lipid 1,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP). A small number of astrocytes and microglial cells were found to be labeled by the oligonucleotides, but only at later times after the injection and exclusively in a punctate cytoplasmic manner. Thus, the uptake of oligonucleotides in the nerve and glial cell populations of the brain might involve different mechanisms, the one in the neurons appearing to be very rapid and potent.

Production and characterization of an iminoimidazolidine specific monoclonal antibody using para-aminoclonidine as antigen.

Para-aminoclonidine coupled to hemocyanin was used to produce mouse monoclonal antibodies directed against clonidine. The properties of one of these, called mFE7, secreted by a clone of hybrid myeloma, are described. This antibody displayed total crossreactivity with imidazolidines and no crossreactivity at all with catecholamines or other known naturally occurring substances tested. A liquid phase radioimmunoassay permitted the detection of immunoreactivity in human brain extracts. The mFE7 antibody could be useful for immunopurifying the endogenous ligand of Imidazolines Preferring Receptors (IPR) which are catecholamines insensitive.

Production and characterization of anti-clonidine antibodies not cross-reacting with catecholamines.

Polyclonal antibodies against clonidine were developed, with para-aminoclonidine coupled to bovine serumalbumin or hemocyanine with glutaraldehyde used as antigens. The selected antibody (from rabbits) cross-reacted with high specificity with clonidine and its structurally closely related analogues but it recognized neither catecholamines nor various endogenous imidazole molecules such as histamine, purine, adenine, and adenosine, thus appearing to be specific for the aminoimidazoline structure. An interesting cross-reactivity was observed with the bovine clonidine displacing substance, the probable endogenous ligand for receptors involved in the hypotensive effect of clonidine-type substances. This suggested that this molecule should contain an aminoimidazoline or guanidine moiety.