Therapeutic studies in NZB/W mice. I. Synergy of azathioprine,cyclophosphamide and methylprednisolone in combination

This study compares different immunosuppressive regimens in the treatment of the lupus-like nephritis of NZB/W mice. Groups of 5-month-old female NZB/W mice were given azathioprine, cyclophosphamide and methylprednisolone in all one-, two- and three-drug regimens, each drug in the relatively low dose of 1.5 mg/kg/day. Treatment for 3 months with one or two drugs resulted in modest suppression of NZB/W disease. Mice receiving all three drugs had significantly less proteinuria, lower titers of anti-DNA antibody and less severe, histologically evident renal involvement than mice treated with one or two drugs. Survival at 1 year was 10% for untreated controls, 44% for one-drug-treated, 37% for two-drug-treated and 86% for the three-drug-treated mice. The survival for the three-drug regimen was significantly longer than any other group (P < 0.01). The three-drug regimen was synergistic, since mice treated with each drug at three times the dose had significantly more proteinuria after 3 months of treatment and lowered 1 year survival (33%). The beneficial effects of triple-drug therapy were attained without increased toxicity. This study represents the first controlled evaluation of single versus combination therapy in a model of autoimmune disease. Based on these results, a controlled evaluation of triple-drug therapy in human systemic lupus erythematosus appears warranted.     

Increased spontaneous activity of antibody-forming cells in the peripheral blood of patients with active sle

Thirty-seven patients with criteria for systemic lupus erythematosus (SLE) and 18 normal controls were studied for their spontaneous background IgM antibody plaque-forming cell number to specific chemical haptens. Active SLE patients had significantly more plaque-forming cells in their peripheral blood to a total of five chemical determinants than did patients with inactive disease or controls. This increased number of plaque forming-cells correlated with depressed serum C3 levels by Spearman rank-order analysis. The finding of elevated numbers of spontaneous IgM plaque-forming cells to defined chemical haptens supports the concept that active SLE demonstrates a generalized increase in B-cell activity toward a variety of antigens.     

Mechanical endothelial damage results in basic fibroblast growth factor-mediated activation of extracellular signal-regulated kinases.

BACKGROUND: Endothelial damage, such as that associated with balloon angioplasty or preparation of veins for bypass grafts, results in intimal hyperplasia. Growth factors and cytokines that modulate endothelial cell functions through various intracellular signaling pathways mediate rapid endothelial repair, which may prevent or reduce restenosis. Here we investigated the effect of mechanical injury of endothelial cells on the mitogen-activated kinase signaling pathways, extracellular-signal-regulated kinases (ERKs), C-Jun N-terminal kinase (JNK/SAPK), and p38. METHODS: Confluent human umbilical vein endothelial cells or bovine aortic endothelial cells were wounded with a razor blade; mitogen-activated kinase activation was monitored by immunoblotting with antibodies to active ERK, JNK/SAPK, or p38. RESULTS: Wounding of human umbilical vein endothelial cell or bovine aortic endothelial cell monolayers resulted in rapid (5-minute) activation of ERK-1 and -2, which was abolished by monoclonal antibody to basic fibroblast growth factor (FGF-2). This antibody or an inhibitor of ERK activation, PD98059, also blocked endothelial cell migration after the wounding. Thus FGF-2-induced ERK activation mediates the endothelial response to wounding. CONCLUSIONS: ERK-1 and -2 are activated by FGF-2 released from endothelial cells in response to injury. Therapeutic strategies aimed at reducing FGF-2-induced intimal hyperplasia should preserve ERK activation in endothelial cells while abolishing it in smooth muscle cells.     

Study of thymic factors. II. Failure of thymosin to alter the natural history of nzb and nzb/nzw mice

The effects of daily injections of thymosin, bovine fraction V, on the natural history of NZB and NZB/NZW F₁ mice were investigated. With the use of several dose schedules, no significant differences were discovered in treated versus control groups when survival, autoantibodies, and mitogen responsiveness were compared. These results provide further evidence that thymosin may have little or no role in the treatment of the autoimmune disease of New Zealand mice. More encouraging research in thymic extracts and their measurement is necessary before clinical trials in SLE are considered.     

qMRI relaxometry of mandibular bone marrow: A monomodal distribution in sickle cell disease

Purpose:

To identify and characterize sickle cell disease (SCD)‐related changes in the composition of mandibular bone marrow using qMRI relaxometry histograms.

Materials and Methods:

Thirteen SCD patients and 17 controls underwent brain MR imaging with the mixed turbo spin‐echo (TSE) pulse sequence at 1.5T. The mandible was manually segmented and divided into body, angle, ramus, and condyle. T1 and T2 histograms of each mandible were modeled with Gaussian functions. The relaxation time histogram peaks were calculated, and the number of monomodal versus bimodal curves was compared.

Results:

SCD patients exhibited monomodal distributions on both T1 and T2 histograms, consistent with a composition of predominantly red hematopoietic marrow. Eighty‐eight percent of mandibles in control subjects exhibited a bimodal distribution in T1 and all showed a bimodal distribution in T2, indicating mixed but predominantly yellow marrow composition. The second peak in control subjects was shorter in T1 and longer in T2, consistent with yellow marrow composition.

Conclusion:

Instead of physiological fatty replacement, SCD patients exhibit red marrow persistence in the mandible, likely due to the increased demand for hematopoiesis. This phenomenon can be manifested by a monomodal curve in both T1 and T2 relaxometric histograms. J. Magn. Reson. Imaging 2013;37:1182–1188. © 2012 Wiley Periodicals, Inc.     

Results of randomized controlled trials of low-versus high-osmolality contrast media

The authors reviewed 100 randomized controlled trials (RCTs) conducted in humans to compare safety or efficacy of new low-osmolality contrast media (LOM) with that of high-osmolality contrast media (HOM). Findings of the 43 RCTs judged to be of the highest quality suggest that the efficacy of LOM in imaging is equal or superior to that of HOM for all routes of administration. Heat sensation occurred less often with LOM for all routes and pain occurred less often with LOM for intraarterial routes. No differences were seen in nephrotoxicity or in frequency of nausea, vomiting, urticaria, bronchospasm, laboratory test abnormalities, or neurologic events. Greater cardiovascular changes were seen with HOM, including increased or decreased heart rate, increased left ventricular end-diastolic pressure, decreased systolic pressure, and QT prolongation, depending on route of administration. To demonstrate whether a reduction in clinically significant adverse outcomes truly occurs with LOM, trials will need to enlist larger numbers of patients and employ appropriate outcome measures. Future trials should stratify patients according to their risk of adverse reactions to provide better information about benefits of LOM in low- versus high-risk patients.