A 6.75-kilobase human hepatoma-derived basic fibroblast growth factor (bFGF) cDNA was cloned and sequenced. An amino-terminal sequence generated from a purified hepatoma bFGF was found to correspond to the nucleotide sequence and to begin 8 amino acids upstream from the putative methionine start codon thought to initiate a 154-amino acid bFGF translation product. This sequence suggests that a form of bFGF of at least 163 amino acids exists. The hepatoma cDNA was transcribed in vitro into RNA; in vitro translation of this RNA generated three forms of bFGF with molecular masses of 18, 21, and 22.5 kDa. By use of in vitro mutagenesis, it was found that the 22.5-kDa bFGF and possibly the 21-kDa form were initiated with CUG start codons. The 18-kDa bFGF was initiated with an AUG codon. By transfecting into COS cells human hepatoma bFGF cDNA and a construct from which the AUG initiator was eliminated, it was found that the higher molecular mass forms of bFGF were as biologically active as the 18-kDa form.

The cellular action of growth factors, among them basic fibroblast growth factor (bFGF), is mediated by their interaction with a cell surface receptor, but the mechanism of transfer of mitogenic (or other) signals to the nucleus has not been identified. In this work, we show that bFGF is translocated to and accumulated in the nucleolus. Furthermore, the nucleolar localization of bFGF is correlated with a stimulation of transcription of ribosomal genes during Gq-.Gl transition induced by bFGF alone in adult bovine aortic endothelial cells (ABAE cells). Stimulation of ribosomal gene transcription is preceded by a significant increase of the major nonhistone nucleolar protein, nucleolin. In vitro, the growth factor has a direct effect on the enhancement of RNA polymerase I activity in isolated nuclei from quiescent sparse (GO) ABAE cells. The direct action of bFGF on the level of ribosomal gene transcription could correspond to an additional growthsignaling pathway, mediated by this growth factor.The family of fibroblast growth factors (FGFs) includes the factors described as endothelial cell growth factor, chondrosarcoma growth factor, and heparin-binding growth factors (1). Preliminary physical analysis of some of these mitogens has suggested their classification in two groups: acidic fibroblast growth factors (aFGFs) (2) and basic fibroblast growth factors (bFGFs) (3). In vitro, aFGFs and bFGFs are potent mitogens for a wide variety of mesoderm-and neuroectoderm-derived cells, including vascular and capillary endothelial cells (4) and, as in vivo (5), they induce the angiogenic response (6).The cellular action of FGFs is exerted through its interaction with specific cell surface receptors (7,8), but the intervening steps and the mechanism of transfer of mitogenic (or other) signals to the nucleus, leading to the "ple-otropic response" required to bring quiescent cells into full proliferation, are at present unknown.The proliferation state and ribosome biogenesis, which involve a series of coordinated nucleolar events, among them the transcription of ribosomal genes (rDNA), are closely related. The level of transcription of rDNA is modulated by cell growth conditions, growth-promoting hormones (9), and growth factors (10). A specific nucleolar protein, nucleolin, was shown in different eukaryotic cells to play a direct role in the control of the synthesis of the precursor to ribosomal RNA (pre-rRNA) and assembly of ribosomes (11,12). Barely detectable in resting cells, nucleolin represents up to 5% of nucleolar proteins in exponentially growing cells. In vitro, run-off experiments with rDNA as template have shown that endoproteolytic cleavage of phosphorylated nucleolin controls rDNA transcription (13).In this report, we have focused on the effects of bFGF on the reinitiation of ribosome biogenesis in cells undergoing the Gy-3G1 transition. We show by immunocytochemistry using a monospecific polyclonal anti-bFGF antibody that the reinitiation of pre-rRNA synthesis is preceded by the accumulation of nucleo...

Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well-tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.

When used in external pumps, LP provides better glycemic control and stability than regular insulin and does not increase the frequency of hypoglycemic episodes.

According to the results of the Diabetes Control and Complications Trial (DCCT) (1), intensive diabetes management should be proposed for most type 1 diabetic patients to prevent long-term complications. However, the ideal insulin regimen should simultaneously achieve 2 goals: maintenance of near-euglycemia and avoidance of frequent and severe hypoglycemia.Several studies have suggested that continuous subcutaneous insulin infusion (CSII) could provide better glycemic control (2-4) with a lower risk of hypoglycemia (5,6) than multiple daily injections (MDI). But very few of these studies were randomized, and all used regular insulin. We and others (7-9) also reported that, when used in external pumps, the shortacting insulin analog lispro provided better glycemic control than regular insulin without increasing the frequency of hypoglycemic episodes.However, to the best of our knowledge, the benefits of lispro use in CSII and MDI have never been compared. Therefore, the aim of the present work was to compare the efficacy on glycemic control and hypoglycemia frequency of 2 new intensified insulin regimens, CSII and MDI, with insulin lispro in a randomized study. RESEARCH DESIGN AND METHODS -The study protocol was approved by the Ethics Committee of Toulouse, and all of the patients gave written consent. PatientsA total of 41 type 1 diabetic patients between 21 and 65 years of age participated in the study. At enrollment, 32 were treated by CSII with regular insulin and 9 by MDI with regular insulin or insulin lispro. The inclusion criteria were HbA 1c Ͻ10.0%, negative C-peptide, and experience of intensified Comparison of Continuous Subcutaneous Insulin Infusion and Multiple Daily Injection Regimens Using Insulin Lispro in Type 1 Diabetic Patients on Intensified TreatmentA randomized study O R I G I N A L A R T I C L EOBJECTIVE -To compare the efficacy of 2 intensified insulin regimens, continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI), by using the short-acting insulin analog lispro in type 1 diabetic patients. RESEARCH DESIGN AND METHODS-A total of 41 C-peptide-negative type 1 diabetic patients (age 43.5 ± 10.3 years; 21 men and 20 women, BMI 24.0 ± 2.4 kg/m 2 , diabetes duration 20.0 ± 11.3 years) on intensified insulin therapy (MDI with regular insulin or lispro, n = 9; CSII with regular insulin, n = 32) were included in an open-label randomized crossover study comparing two 4-month periods of intensified insulin therapy with lispro: one period by MDI and the other by CSII. Blood glucose (BG) was monitored before and after each of the 3 meals each day.RESULTS -The basal insulin regimen had to be optimized in 75% of the patients during the MDI period (mean number of NPH injections per day = 2.65). HbA 1c values were lower when lispro was used in CSII than in MDI (7.89 ± 0.77 vs. 8.24 ± 0.77%, P Ͻ 0.001). BG levels were lower with CSII (165 ± 27 vs. 175 ± 33 mg/dl, P Ͻ 0.05). The SD of all the BG values (73 ± 15 vs. 82 ± 18 mg/dl, P Ͻ 0.01) was lower with CSII. The frequency of...