Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.
Pleiotrophin (PTN) was found to regulate tyrosine phosphorylation of -adducin through the PTN͞receptor protein tyrosine phosphatase (RPTP)͞ signaling pathway. We now demonstrate that PTN stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (PK) C substrate domain of -adducin through activation of either PKC ␣ or . We also demonstrate that PTN stimulates translocation of phosphoserine 713 and 726 -adducin either to nuclei, where it associates with nuclear chromatin and with centrioles of dividing cells, or to a membrane-associated site, depending on the phase of cell growth. Furthermore, we demonstrate that PTN stimulates the degradation of -adducin in PTN-stimulated cells. Phosphorylation of serines 713 and 726 in -adducin is known to markedly reduce the affinity of -adducin for spectrin and actin and to uncouple actin͞spectrin͞ -adducin multimeric complexes needed for cytoskeletal stability. The Ptn gene also is a proto-oncogene (12, 13). Its high-level importance in human malignancies is suggested because expression of the endogenous Ptn gene is seen frequently in many different highly malignant human neoplasms (14-22), and introduction of a dominant negative Ptn gene or targeted ribozymes into cells from malignancies with constitutive expression of the Ptn gene reverses the malignant phenotype to the phenotype of the premalignant cells both in vivo and in vitro, indicating that PTN signaling is responsible for the ''switch'' of the premalignant cell to the highly malignant phenotype (11,12,21,23,24).Recent studies have uncovered clues to the mechanisms by which PTN initiates this striking diversity of phenotypes in PTN-stimulated cells. Pleiotrophin signals through two functionally and structurally independent signaling domains (refs. 5, 11, and 12 and N. Zhang, R. Zhong, Z. Y. Wang, and T.F.D., unpublished data), each of which binds heparin (25), and each of which signals very different phenotypes. The N-terminal domain, when expressed with the endogenous signal peptide, transforms murine fibroblasts, whereas the C-terminal domain does not; however, the C-terminal domain of PTN induces rapid growth and a striking angiogenic phenotype when it is expressed with the endogenous signal peptide in the premalignant cell. Thus, the separate domains of PTN function independently of each other, signal different phenotypes, and, a priori, need to signal through two separate receptor-like proteins (5,11,12).One receptor that initiates PTN signaling is the transmembrane receptor protein tyrosine phosphatase (RPTP) ͞. The interaction of PTN with RPTP͞ induces receptor dimerization and inactivates the endogenous tyrosine phosphatase activity of RPTP͞, thereby disrupting the balanced activity of RPTP͞ and an unknown but constitutively active tyrosine kinase(s) on the mutual substrates of RPTP͞ and the tyrosine kinase and thus initiating a sharp and rapid increase in the steady state levels of tyrosine phosphorylation (26). The first substrate of RPTP͞ to be id...
SummaryWe have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average 59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%.PurposeTo characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain.MethodsDesign: prospective cohort study. Consecutive sample of patients ≥ 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described.ResultsA total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively.ConclusionsDespite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis.Electronic supplementary materialThe online version of this article (10.1007/s11657-018-0515-8) contains supplementary material, which is available to authorized users.
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