A total of 313 patients with childhood acute leukemia received a combination of vincristine (2 mg/m2/week) and prednisone (60 mg/m2/day); 86% of 276 evaluable patients achieved a complete bone marrow remission in a median of 35 days. When a complete bone marrow remission was achieved, patients were randomized to one of three oral maintenance therapies: 6-mercaptopurine (6MP) (75 mg/m2/day), methotrexate (MTX) (25 mg/m2/twice weekly), or cyclophosphamide (CYC) (100 mg/m2/day). Patients receiving maintenance therapy were further randomized at 2 and 6 months after the start of maintenance either to continue or discontinue therapy. The median lengths of subsequent bone marrow remission for patients randomized at 2 months to continue vs. discontinue therapy were: 37 vs. 19 weeks for 6-MP patients; 25 vs. 14 weeks for MTX patients; and 29 vs. 13 weeks for CYC patients. The median lengths of subsequent marrow remissions for patients receiving maintenance therapy for 6 months and randomized to continue vs. discontinue were: 57 vs. 17 weeks for 6-MP patients; 60 vs. 40 weeks for MTX patients; and 23 vs. 10 weeks for CYC patients. Results indicate a significant advantage for continuing maintenance therapy at 2 and 6 months after the start of complete bone marrow remission.
Each of 105 children with advanced acute leukemia in relapse was randomly assigned to one of three treatment schedules utilizing L-asparaginase. L-asparaginase used alone induced bone marrow remissions in 43% of all cases and 54% of evaluable cases. L-asparaginase combined with vincristine and prednisone induced remissions in a significantly greater number of children—50% of all cases and 77% of evaluable cases: There was a suggestive advantage in survival experience for patients receiving the 3-drug combination compared with L-asparaginase alone. Survival in this study population was clearly related to the length of disease prior to start of therapy, the longer survivals occurring in those with longer prestudy duration of disease. Fourteen of 17 children who had relapsed following inductions of remissions with the first course of L-asparaginase treatment had remissions again following retreatment with a second course. These results indicate that L-asparaginase has considerable therapeutic activity in children with advanced leukemia.
A 3-year-old boy with minor bleeding problems had no plasma fibrinogen measured by both clottable assay and immuno-precipitation. Low normal fibrinogen levels were present in the mother and father. Markedly decreased plasma cholesterol and apolipoprotein B levels were found in the father, proband's brother, and the paternal side of the kindred. The proband and his mother had normal plasma total cholesterol and apolipoprotein B levels. These findings are compatible with autosomal dominant transmission of hypobetalipoproteinemia and autosomal recessive transmission of afibrinogenemia. Two members of the father's family had plasma cholesterol levels below the fifth percentile but elevated levels of fibrinogen (6.0 and 4.4 g/L). Both have symptomatic coronary heart disease. Finding coronary heart disease with very low cholesterol but elevated fibrinogen levels is consistent with fibrinogen levels being an independent risk factor for coronary heart disease.
The 3T3-L1 adipocyte differentiation system is a reliable in vitro model for adipogenesis in vivo. Under the controlled conditions of cell culture, 3T3-L1 preadipocytes can be induced (with appropriate hormonal agents) to differentiate into cells that have the biochemical and morphological characteristics of tissue adipocytes. We have identified, cloned, and characterized a number of adipocyte genes that are coordinately activated during differentiation and contribute to acquisition of the adipocyte phenotype. C/EBPα serves as a pleiotropic transcriptional activator of these and many other adipocyte genes. Expression of C/EBPα is not only required for, but is sufficient (in combination with PPARγ) to activate the differentiation program of 3T3-L1 preadipocytes without the use of hormonal agents. In view of the importance of C/EBPα in adipocyte differentiation, we have begun to characterize the promoter of the C/EBPα gene. In addition to a C/EBP regulatory element in the proximal promoter of the gene, we have identified three repressor binding sites. A differentially expressed nuclear factor that binds to two of these sites has been isolated and characterized. This factor, referred to as CUP (C/EBPα Undifferentiated Protein), is expressed by preadipocytes but not adipocytes. Both the mouse and human C/EBPα genes possess two CUP binding sites, one in the 5′-flanking and another in the 5′-untranslated region of the genes. Mutation of either CUP site individually has little effect on reporter gene transcription mediated by the promoter; however, when both CUP sites are mutated marked synergistic “derepression” occurs. We have purified CUP from 3T3-L1 preadipocytes and shown it to be an isoform of the transcription factor AP-2α. Forced expression of the AP-2α1 isoform in adipocytes, which normally do not express this factor, inhibits reporter gene transcription mediated by the C/EBPα promoter. Our findings indicate that CUP/AP-2α is a repressor of the C/EBPα gene promoter and suggest that this factor maintains the gene in a repressed state prior to differentiation. A binding site (a GC box) for another repressor has been identified at the 5′-end of the C/EBP regulatory element in the C/EBPα promoter. The transcription factor Sp1, which is expressed by preadipocytes, was found to bind at this site. By binding at this site, Sp1 sterically can block access to the C/EBP binding site by members of the C/EBP family. Thus, transcriptional activation of the C/EBPα a gene by C/EBPβ (and possibly C/EBPδ), which is thought to occur early in the adipocyte differentiation program, would be prevented. Consistent with this view, transactivation of C/EBPα promoter by C/EBPβ is inhibited by Sp1. Preliminary evidence indicates that the differentiation inducers increase the rate of turnover of Sp1. Lowering the Sp1 level early in the differentiation program would facilitate binding of C/EBPβ to the C/EBP regulatory element and, thereby, transcriptional activation of the C/EBPα gene.
The criticism of antenatal formula advertising by Howard et al1 regrettably reflects how ignorant many pediatricians are about breast-feeding in the community setting. Having been involved in infant nutrition studies on a face-to-face basis for more than 10 years,2 our experience indicates that formula advertising plays an insignificant role in reducing the frequency of breast-feeding among new mothers. Most information about infant nutrition is provided to American mothers through hospitals' prenatal classes run by Departments of Obstetrics.
Objective: The purpose of this study was to evaluate the effects of birth weight on cord serum lipid and apolipoprotein levels in preterm infants with and without respiratory distress syndrome (RDS). Methods: Cord serum lipid and apolipoprotein levels were evaluated in preterm infants (39 with RDS and 68 controls without RDS). Based on morbidity and mortality risk, RDS and non-RDS infants were separated into four birth weight groups (2000-2499 g, 1500-1999 g, 1000-1499 g, < 1000 g) and evaluated for effects of birth weight on cord serum levels. Results: RDS infants with birth weight of 2000-2499 g had significantly higher levels of cholesterol, triglyceride, total fatty acids and apolipoprotein A-I, but not arachidonic acid, than controls. RDS infants weighing 1000-1999 g had lower total fatty acids and apolipoprotein B levels, including arachidonic acid, than non-RDS infants. Cord serum lipid and apolipoprotein levels were significantly elevated in large (2000-2499 g) RDS infants, but lower levels were found in smaller (1000-1999 g) RDS infants. Conclusions: Cord serum arachidonic acid and apolipoprotein levels found in RDS infants suggest that lipid transport across the placenta may be abnormal. Inadequate total fatty acid supplies in utero could interfere with normal fetal growth and maturation, leading to development of neonatal RDS as one manifestation of risk for postnatal morbidity and mortality.
