Induction of B cell tolerance to polysaccharides by exhaustive immunization and during immunosuppression with cyclophosphamide

Mice immunized with an optimal (10 μg), but not suboptimal, dose of levan (LE) became specifically unresponsive to a second dose given 2–8 weeks later. No evidence which could implicate an active suppression mechanism was found. In particular (a) spleen cells from unresponsive donors did not inhibit normal cells in a transfer system; (b) equilibration of serum antibody following 2 days celomic parabiosis between LE-treated and normal mice did not impair responsiveness of the latter. It was concluded that B cells were exhausted in the absence of memory cell accumulation. LE can therefore induce specific B cell deletion, not only directly with 1 mg, but also following immunization with 10 μg. The exhaustive capacity of another polysaccharide, SIII, was found to be much weaker. Cyclophosphamide (CP) (150 mg/kg) completely suppressed the responses to LE and SIII when injected with them. Recovery following CP alone was nearly complete 2 weeks later, but simultaneous injection of an immunizing amount of LE was succeeded by dose-related specific tolerance. Total suppression followed only 100 ng LE + CP, a 10 000-fold reduction in the “high zone” tolerizing dose. The corresponding reduction in SIII experiments was only 5-fold. The times for recovery following transfer of spleen cells from donors tolerant of LE in the exhaustion and CP models were 2 and 4 weeks, respectively; periods commensurate with B cell renewal. The basis for these further differences in the tolerogenic properties of LE and SIII are discussed.     

Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-l-cysteine

3-Butene-1,2-diol (BDD), an allylic alcohol and major metabolite of 1,3-butadiene, has previously been shown to cause hepatotoxicity and hypoglycemia in male Sprague-Dawley rats, but the mechanisms of toxicity were unclear. In this study, rats were administered BDD (250 mg/kg) or saline, ip, and serum insulin levels, hepatic lactate levels, and hepatic cellular and mitochondrial GSH, GSSG, ATP, and ADP levels were measured 1 or 4 h after treatment. The results show that serum insulin levels were not causing the hypoglycemia and that the hypoglycemia was not caused by an enhancement of the metabolism of pyruvate to lactate because hepatic lactate levels were either similar (1 h) or lower (4 h) than controls. However, both hepatic cellular and mitochondrial GSH and GSSG levels were severely depleted 1 and 4 h after treatment and the mitochondrial ATP/ADP ratio was also lowered 4 h after treatment relative to controls. Because these results suggested a role for hepatic cellular and mitochondrial GSH in BDD toxicity, additional rats were administered N-acetyl-l-cysteine (NAC; 200 mg/kg) 15 min after BDD administration. NAC treatment partially prevented depletion of hepatic cellular and mitochondrial GSH and preserved the mitochondrial ATP/ADP ratio. NAC also prevented the severe depletion of serum glucose concentration and the elevation of serum alanine aminotransferase activity after BDD treatment without affecting the plasma concentration of BDD. Thus, depletion of hepatic cellular and mitochondrial GSH followed by the decrease in the mitochondrial ATP/ADP ratio was likely contributing to the mechanisms of hepatotoxicity and hypoglycemia in the rat.     

Prognostic significance of high grade prostatic intraepithelial neoplasia and atypical small acinar proliferation in the contemporary era

PURPOSE: High grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) in the sextant biopsy had been associated with a high risk of prostate cancer. We determined whether the extended biopsy schemes used in the contemporary era have altered the prognostic value of these lesions at repeat biopsies. MATERIALS AND METHODS: From 1998 to 2003, 105 of 1,188 men had at least 1 repeat extended biopsy due to the presence of HGPIN (33 men) or ASAP (72 men) in a previous extended biopsy. Median biopsy interval for HGPIN and ASAP was 15 and 10 weeks (p <0.05), respectively. Differences in cancer detection rates were analyzed using the Pearson chi-square test. RESULTS: In the HGPIN group only 1 of 22 (4.5%) men had cancer on 1st repeat biopsy and 0 of 11 men had cancer on 2nd repeat biopsy. In men with ASAP 19 of 53 (36%, p <0.005) had cancer on 1st repeat biopsy, and 3 of 19 (16%) had cancer on 2nd repeat biopsy. Cancer was confined to a single core in 16 of 22 (73%) men. Median Gleason score was 6. Patient age, digital rectal examination status, prostate specific antigen, free prostate specific antigen, number of cores and biopsy interval were not independent predictors of cancer in men with ASAP. CONCLUSIONS: HGPIN found in the contemporary extended biopsy does not warrant repeat biopsy. ASAP continues to be associated with a high risk of cancer and requires at least 1 repeat biopsy using the extended biopsy scheme.     

Treatment of distal femoral fractures with early weight-bearing. A preliminary report.

Ten patients with 11 supracondylar fractures of the femur were treated with early weight-bearing and early knee motion. All fractures united. A good functional range of painless knee motion was restored in each case. No deformity or shortening developed during treatment in the cast-brace.