Previous studies reported that a 2- to 3-week course of IV cyclophosphamide plus adrenocorticotropic hormone (ACTH) induction can temporarily halt progressive MS for a period of 12 months in the majority of patients treated, after which reprogression occurs. The Northeast Cooperative Multiple Sclerosis Treatment Group was formed to determine whether outpatient pulse cyclophosphamide therapy could affect reprogression and whether there were differences between a modified induction regimen and the previously published regimen. Two hundred fifty-six progressive MS patients were randomized into four groups to receive IV cyclophosphamide/ACTH via the previously published versus a modified induction regimen, with or without outpatient IV cyclophosphamide boosters (700 mg/m2 every other month for 2 years). There were blinded evaluations performed every 6 months. Results demonstrate that (1) there were no differences between the modified and the published induction regimens either in terms of initial stabilization or subsequent progression; (2) without boosters, the majority of patients continued to progress; and (3) in patients receiving boosters, there was a statistically significant benefit at 24 months and 30 months (p = 0.04). Time to treatment failure after 1 year was also significantly prolonged in the booster versus the nonbooster group (p = 0.03). Age was the most important variable that correlated with response to therapy in that amelioration of disease progression occurred primarily in patients 40 years of age or younger. Boosters had a significant benefit on time to treatment failure in patients ages 18 to 40, p = 0.003, but not in patients ages 41 to 55, p = 0.97.(ABSTRACT TRUNCATED AT 250 WORDS)
Mouse submaxillary gland nerve growth factor (NGF) has been covalently joined to bacteriophage and the resulting phage conjugates remain biologically active in stimulating neurite extension from sensory ganglia. A sensitive bacteriophage immunoassay has been developed to measure concentrations of NGF as low as 1 ng/ml. With this method, we find that mouse L and 3T3 cells in culture produce a biologically active nerve growth factor that is immunologically similar if not identical to mouse submaxillary gland NGF. Since L cels are known to be a source of "conditioned medium" for tissue culture, it could be that one or more of the conditioning factor activities secreted by these cells are due to NGF itself.In the study presented below, several lines of evidence indicate that mouse L and 3T3 cells in culture produce a biologically active nerve growth factor that is similar to (and possibly identical with) the nerve growth factor (NGF) isolated from male mouse submaxillary glands.The L cell fibroblast strain was derived in 1943 from explanted mouse C3H subcutaneous and adipose tissue which had been treated in vitro for several months with 20-methylcholanthrene (1). In 1948, L- L-cells injected into newborn C3H mice produce malignant sarcomas, and in this connection, it will be recalled that the first description of nerve growth factor activity arose from studies with two mouse sarcomas (sarcomas 180 and 37) (4-6). Moreover, extracts of experimentally induced mouse granuloma tissue also display a nerve growth factor activity in vitro (7).These studies are pertinent to the question of where NGF is synthesized in the mouse. For example, the male mouse submaxillary gland contains large amounts of NGF (8) and the growth factor may be synthesized there (9, 10). On the other hand, the radioimmunoassay studies of -Hendry and Iverson demonstrate that submaxillary gland cannot be the sole source of NGF in the adult mouse, since serum levels of the growth factor return to normal 2 months after removal of both submaxillary glands (11 MATERIALS AND METHODSPreparation of Pure NGF. NGF wad purified from a homogenate of 800 male mouse submaxillary glands by two modifications of the method described by Bocchini and Angeletti The other modification involves the carboxymethyl cellulose chromatography step (12). The NGF preparation, dissolved in 0.05 M sodium acetate, pH 5.0, was applied to a 2.4 X 5.4-cm column of CM-52 (Whatman) equilibrated with the same buffer. A step gradient to 0.15 M NaCl was applied to elute most contaminating proteins. Next, a linear NaCl gradient (0.15-2.0 M NaCl; total volume 600 ml; NaCl dissolved in 0.05 M sodium acetate, pH 5.0) was used to elute NGF, which emerged as a single peak at 0.5 N NaCl. Fractions were pooled and protein concentration was measured by the Lowry procedure. Purified NGF was stored in 5-ml aliquots at -15°. These preparations of NGF displayed high biological activity when assayed using sensory ganglia.Gel Electrophoresis. Polyacrylamide gel electrophoresis of the NGF subunit ...
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