Further mapping of the Idd5.1 locus for autoimmune diabetes in NOD mice.

The Idd5 locus for autoimmune diabetes in nonobese diabetic (NOD) mice has been mapped to the proximal half of chromosome 1 and appears to include two loci, Idd5.1 and Idd5.2, Idd5.1 being a candidate homolog of the human IDDM12 locus. Using new recombinant congenic lines, we have reduced the Idd5.1 interval to 5 cM at most, between D1Mit279 and D1Mit19 (not included). This interval now excludes the Casp8 and Cflar (Flip) candidate genes. It still retains Cd28 and Ctla4 and also includes Icos (inducible costimulator). The previously reported differential expression of Ctla4, which is induced at a lower level in NOD than in B6-activated T-cells, was found independent of Idd5.1 itself because Ctla4 expression was induced at a low level in T-cells from Idd5.1-congenic mice. The Idd5.1 locus protected against both spontaneous and cyclophosphamide-induced diabetes, but it did not prevent inflammatory infiltration of the islets of Langerhans. Furthermore, diabetogenic precursor spleen cells from prediabetic NOD and Idd5.1-congenic mice were equally capable of transferring diabetes to immunodeficient NOD.scid/scid recipient mice. The Idd5.1 locus might affect a late event of disease development, subsequent to the onset of insulitis and possibly taking place in the islets of Langerhans.

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x.

Activated lymphocytes of autoimmune non-obese diabetic (NOD) mice exhibit an increased resistance to programmed cell death (PCD) following withdrawal of interleukin-2 (IL-2). In the present study, we found that resistance of NOD T lymphocytes to PCD was increased as early as 1 week of age, hence several weeks before the invasion of the pancreas by inflammatory cells, which is compatible with a role of the NOD apoptotic phenotype in the autoimmune susceptibility of this strain. In the thymus, mature single positive but not double positive or double negative thymocytes were more resistant to PCD in NOD compared to B6 mice. Moreover, in both NOD and B6 mice, CD4+ T cells were more resistant to PCD induced by IL-2 deprivation than CD8+ cells. As a result, NOD CD4+ T cells were remarkably resistant to cell death induced in this manner. In relation with this increased resistance to apoptosis, expression of the anti-apoptotic Bcl-x protein was upregulated in activated T cells of NOD mice, most notably after 24 h of IL-2 deprivation. These results should help us to understand the relationship of the NOD apoptotic phenotype to the emergence of the NOD mouse autoimmune disease.

Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum.

A quantitative trait locus for increased IgG serum levels in the NOD mouse strain was mapped to distal chromosome 1, close to the fcgr2 locus encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII). Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gamma RIIb1) isoform was only slightly decreased and Fc gamma RIII was not altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr2 or by a closely linked locus, occurred at the mRNA level, and was associated with multiple mutations in the fcgr2 gene promoter. In relation with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsonized RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severely impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mice, indicating that Fc gamma RII plays a nondispensable role in binding of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 congenic mice. These findings indicate that macrophage Fc gamma RII may regulate serum IgG1 and IgG2b through their catabolism, and validate the NOD strain as a model to investigate the functions of Fc gamma RII isoforms.

[Initial trial of a new test for the evaluation of hepatocellular function: the TMB test]. / Premiers essais d'un nouveau test d'évaluation du fonctionnement hépatocellulaire: le test au TMB.

The oral administration of 400 mg of trimethoxy 1-3-5-benzene or T.M.B. is normally followed by a high urinary excretion of dimethoxy, 1, 3, hydroxy 5 benzene and other metabolites mainly in the form of conjugates. Urinary excretion during the first 3 hours is strongly reduced in liver disease. By a simple blind test we showed that the test is positive in subclinical and laboratory-negative liver failure.

Blood and urinary concentrations of fosfomycin as a function of the renal function value.

The following parameters were considered in studying 43 subjects under treatment for urinary infections with different degrees of renal insufficiency: the maximum blood concentrations, the plasmatic half-life, and the urinary concentrations of fosfomycin as a function of the plasma creatinine of the subject treated. The curve of the average maximum blood concentrations show a parabola-like increase, the plasmatic half-life followed the same tendency, while the curve of the average urinary concentrations presented an exponential decrease. The urinary concentrations were, nevertheless, always higher than 100 mug/ml regardless of the degree of renal insufficiency and even in the subjects who had a very high plasma creatinine. Given its absence of renal and systemic toxicity, the daily dosage of fosfomycin could remain unchanged regardless of the degree of insufficiency.

Treatment of urinary infections with fosfomycin.

This report deals with the study made of the treatment of 45 acute, subacute and chronic urinary infections in a department of general medicine. 43 of these were infections caused by a single species of bacteria and 3 were caused by more than one species. The sensitivity test of the isolated organisms (E. coli, Proteus, Serratia, Pseudomonas, Klebsiella and S. faecalis) showed 83.33% of the strains to be senstive and 16.8% of the strains to be resistant. Nevertheless, this last group of strains, with the exception of one Pseudomonas, proved to be sensitive to the association of fosfomycin with a beta-lactamin (carbenicillin, amoxycillin) or an aminoglycoside (gentamicin, tobramycin). Of a total of 45 cases, 34 were exclusively treated with fosfomycin (2 g by the intramuscular route and 2 g by the oral route) and 11 cases were treated with a double association of fosfomycin with a beta-lactamin (carbenicillin or amoxycillin) or an aminoglycoside (gentamicin), after having studied the bactericidal activity of the association in vitro. The clinical and bacteriological results were verified 4 weeks after the conclusion of the treatment and showed that there was an eradication of the urinary infection in 34 cases (75.55%), relapses in 6 cases (13.33%) and reinfections in 5 cases (11.22%). These results would seem to be favourable with regards to hospital infections and with respect to organisms that are considered to be very little sensitive or resistant.