Studies on insulin-like growth factors (IGF-I, -II) and there binding proteins in normal human pregnancy

In order to elucidate the roles of Insulin-like Growth Factors (IGF-I, -II) in human pregnancy, the levels of IGF-I and IGF-II, the distribution of binding proteins for IGF-I or IGF-II and profiles of unsaturated somatomedin binding proteins (USBP) were estimated in maternal and cord plasma. IGF-I levels in maternal plasma gradually elevated in late gestation, reaching 304.4 +/- 130.1ng/ml at term, and were significantly higher than those in nonpregnant women (188 +/- 58). IGF-II levels, which were 414.9 +/- 75.4ng/ml in women in the third trimester of gestation, did not produce any remarkable changes in the levels in nonpregnant women (395.9 +/- 72.6). On the other hand, IGF-I in cord plasma also increased according to gestational age, reaching 37.3 +/- 14.6ng/ml at term, but it was significantly lower than that in maternal weight (r = 0.50, p less than 0.005) and relative birth weight (r = 0.41, p less than 0.005). IGF-II in cord plasma showed no significant changes during gestation, however, IGF-II levels in AFD (appropriate for date) newborns delivered at term (203.8 +/- 59.4) were significantly lower than those in maternal plasma. And they had no positive correlations with birth weight and relative birth weight. On Sephadex G150 gel-chromatography of cord plasma from AFD newborns at term, more than 70% of immunoreactive IGF-I in plasma was eluted at 150K region, and 150K USBP could be detected as observed in adult plasma. On the other hand, most of the immunoreactive IGF-II was eluted at 40K region, and 150K USBP was not detected in AFD newborns at term. In adult plasma, most of the immunoreactive IGF-II was eluted at 150K region, but 150K USBP could not be detected. From these results, it is supposed that IGF-I plays an essential role in fetal growth rather than IGF-II.     

Reproducibility of head-up tilt-table testing for eliciting susceptibility to neurally mediated syncope in patients without structural heart disease.

Head-up tilt testing has gained acceptance as a tool for assessing susceptibility to neurally mediated syncopal syndromes (e.g., vasovagal syncope), and is currently being evaluated as a means of testing therapeutic interventions in these conditions. To assess reproducibility of head-up tilt testing and thereby assess the potential of such testing for immediate evaluation of a planned treatment, findings during 2 sequential 80 degrees head-up tilt tests were compared in 23 patients (age range 6.5 to 74 years) undergoing evaluation of syncope of unknown origin. Upright tilt was performed initially in the absence of drugs, and repeated if necessary during pharmacologic provocation by means of isoproterenol infusions of 1 and 3 micrograms/min (tilt 1). End points were syncope, maximal tolerated isoproterenol dose, or a tilt duration of 10 minutes. The second tilt test (tilt 2) was conducted after approximately 30 minutes of supine rest using the maximal provocative conditions used in tilt 1. Fifteen of 23 patients (65%) developed syncope in either tilt 1 or 2, while 8 of 23 (35%) remained asymptomatic. Tilt testing results were concordant (i.e., positive in both tests, or negative in both tests) in 20 of 23 (87%) patients. Concordance was, however, less among tilt-positive patients (12 of 15, 80%) since 3 patients were tilt-positive in tilt 1 only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Src family kinases and nitric oxide production are required for hepatocyte growth factor-stimulated endothelial cell growth

Hepatocyte growth factor (HGF) is a potent mitogen for vascular endothelial cells (EC); however, signal transduction pathways for HGF-stimulated EC growth remain unclear. In the present study we investigated the role of Src family kinases and nitric oxide (NO) in HGF-stimulated EC growth. Human umbilical vein endothelial cells (HUVEC) were stimulated with HGF and NO was measured by an NOx analyzing HPLC system. Activation of ERK1/2 and p38 MAPK was assessed by Western blot. NO production in HUVEC increased 1.8-fold by HGF. A Src family kinases inhibitor PP1 inhibited HGF-stimulated NO production by 71%. HUVEC growth increased 1.9-fold in cell number by HGF. PP1 and Nitro-L-arginine methylester (L-NAME) inhibited HGF-stimulated HUVEC growth by 51 and by 71%. ERK1/2 and p38 MAPK were phosphorylated by HGF and a MEK inhibitor PD98059 and a p38 MAPK inhibitor SB203580 inhibited HGF-stimulated HUVEC growth by 66% and by 58%; however, HGF-induced phosphorylation of ERK1/2 and p38 MAPK was not inhibited by L-NAME, indicating that NO is not an upstream activator of ERK1/2 and p38 MAPK. These findings demonstrated that Src family kinases regulate HGF-stimulated NO production in HUVEC and that HGF stimulates HUVEC growth through NO-dependent and NO-independent pathways.     

Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration

Stem cell factor (SCF) has crucial roles in proliferation, survival, and differentiation of hematopoietic stem cells and mast cells through binding to c-Kit receptor (KIT). Chemotaxis is another unique function of SCF. However, little is known about the intracellular signaling pathway of SCF/KIT-mediated cell migration. To investigate the signaling cascade, we made a series of 22 KIT mutants, in which tyrosine (Y) residue was substituted for phenylalanine (F) in the cytoplasmic domain, and introduced into BAF3 cells or 293T cells. On stimulation with SCF, BAF3 expressing KIT(WT)(WT) showed cell migration and Ca(2+) mobilization. Among 22 YF mutants, Y567F, Y569F, and Y719F showed significantly reduced cell migration and Ca(2+) mobilization compared to WT. In Y567F, Lyn activation on SCF stimulation decreased and C-terminal Src kinase (Csk) suppressed KIT-mediated Ca(2+) influx and cell migration, suggesting that Y567-mediated Src family kinase (SFK) activation leads to Ca(2+) influx and migration. Furthermore, we found that p38 mitogen-activated protein kinase (p38 MAPK) and Erk1/2 were also regulated by Y567/SFK and involved in cell migration, and that p38 MAPK induced Ca(2+) influx, thereby leading to Erk1/2 activation. In Y719F, the binding of phosphatidylinositol 3'-kinase (PI3K) to KIT was lost and KIT-mediated cell migration and Ca(2+) mobilization were suppressed by PI3K chemical inhibitors or dominant-negative PI3K, suggesting the involvement of Y719-mediated PI3K pathway in cell migration. Combination of Csk and the PI3K inhibitor synergistically reduced cell migration, suggesting the cooperation of SFK and PI3K. Taken together, these results indicate that 2 major KIT signaling pathways lead to cell migration, one is Y567-SFK-p38 MAPK-Ca(2+) influx-Erk and the other is Y719-PI3K-Ca(2+) influx.     

Evolution to acute myeloblastic leukemia from chronic neutrophilic leukemia with dysplastic features in granulocytic lineage

We experienced the case of an 82-year-old man with chronic neutrophilic leukemia (CNL) with dysplastic features in the granulocytic lineage which subsequently progressed to acute myeloblastic leukemia (AML) with myelofibrosis. The patient had hepatosplenomegaly, but there was no evident cause of neutrophilic leukocytosis. The cytogenetic study showed that he had a normal karyotype. Concentrations of the serum granulocyte colony-stimulating factor (G-CSF) were not detectable. Two years after the diagnosis of CNL, blastic transformation to AML occurred with myelofibrosis and significant morphological abnormalities in neutrophils. The blasts were positive for myeloperoxidase, CD33, CD34, and HLA-DR, and the presence of dysplasia within the granulocytic lineage suggested that he had an abnormality at the level of the granulocyte-committed progenitors. Heterogeneous origins of CNL might lead to various clinicopathological features in each case.     

Percutaneous transhepatic gallbladder stenting for recurrent acute acalculous cholecystitis after failed endoscopic attempt

Endoscopic gallbladder stenting is useful palliative therapy for acute cholecystitis in high‐risk patients. Although the success rate of endoscopic gallbladder stenting is 79%–100%, an alternative method has not been reported. We succeeded in employing a method for percutaneous gallbladder stenting (PTGS) and herein describe this new method. A patient with acute acalculous cholecystitis related to ischemic atherosclerotic vascular disease, cholangitis due to Lemmel syndrome, and severe congestive heart failure underwent PTGS through the cystic duct from the gallbladder to the duodenal papilla, because an endoscopic method failed in the treatment of Lemmel syndrome. Because we were unable to place endoscopic transpapillary gallbladder drainage, percutaneous transhepatic gallbladder drainage (PTGBD) was performed and both the cholecystitis and cholangitis ceased. PTGS was performed as an alternative to endoscopic gallbladder stenting. Access to the cystic duct and gallbladder was obtained by the PTGBD route, using a guidewire (0.035‐inch diameter) and seeking catheter (6.5 Fr) under fluoroscopic control. A 7‐Fr 12‐cm double‐pigtail biliary polyethylene stent was placed. The patient remained asymptomatic for 3 months after the PTGS until he died, of an acute recurrent myocardial infarction. This new PTGS placement is an alternative treatment for symptomatic gallbladder disease in patients with increased operative risk when the endoscopic method is unsuccessful.     

Vascular remodeling and plaque composition between focal and diffuse coronary lesions assessed by intravascular ultrasound

Coronary remodeling and plaque composition were compared between focal and diffuse coronary lesions. Negative remodeling and fibrous and calcified plaque compositions contribute to stenosis development in diffuse lesions more frequently than in focal lesions.