Range of Movement for Impingement and Dislocation Avoidance in Total Hip Replacement Predicted by Finite Element Model.

Dislocation is a serious complication in total hip replacement (THR). An inadequate range of movement (ROM) can lead to impingement of the prosthesis neck on the acetabular cup; furthermore, the initiation of subluxation and dislocation may occur. The objective of this study was to generate a parametric three-dimensional finite element (FE) model capable of predicting the dislocation stability for various positions of the prosthetic head, neck, and cup under various activities.

Uncovering new pharmacological targets to treat neuropathic pain by understanding how the organism reacts to nerve injury.

The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term.

The neurotrophic factor pleiotrophin modulates amphetamine-seeking behaviour and amphetamine-induced neurotoxic effects: evidence from pleiotrophin knockout mice.

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.

Blocking receptor protein tyrosine phosphatase beta/zeta: a potential therapeutic strategy for Parkinson's disease.

striatum of rodents in experimental models of Parkinson's disease. Interestingly, immunohistochemical studies have shown increased levels of PTN expression in the substantia nigra of patients with Parkinson's disease. Since, in other contexts, PTN has been shown to be critical in repair processes in the injured nervous system, the antecedents suggest that PTN could exhibit protective effects in Parkinson's disease.

Targeting the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta signaling pathway to limit neurotoxicity induced by drug abuse.

This review compiles the scientific basis to propose the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta signaling pathway as a new therapeutic target to prevent drug of abuse-induced toxicity. In addition, potential guidelines are provided for the development of new therapeutic compounds derived from that knowledge. This approach may be relevant since efficient therapeutic strategies are currently lacking in this field, even when drug-induced neurotoxicity seems to underlie the neurodegenerative disorders diagnosed in drug addicts.

Noradrenergic and opioidergic alterations in neuropathy in different rat strains.

The Fischer 344 (F344) rat strain differs from the Lewis strain in the response to neuropathic pain. Recently, we found that F344 rats totally recover from mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve 28 days after surgery whereas Lewis rats are initiating their recovery at this time point. Thus, the use of this neuropathic pain model in these different rat strains constitutes a good strategy to identify possible target genes involved in the development of neuropathic pain.

Different pattern of pleiotrophin and midkine expression in neuropathic pain: correlation between changes in pleiotrophin gene expression and rat strain differences in neuropathic pain.

Pleiotrophin (PTN) and midkine (MK) are two growth factors highly redundant in function that exhibit neurotrophic actions and are upregulated at sites of nerve injury, both properties being compatible with a potential involvement in the pathophysiological events that follow nerve damage (i.e. neuropathic pain).

Changes in BDNF gene expression correlate with rat strain differences in neuropathic pain.

The Fischer 344 (F344) rat inbred strain differs from the inbred Lewis and the outbred Sprague-Dawley (SD) in the response to different pain stimuli, which has been partially attributed to differences in the endogenous opioid and noradrenergic systems. Since brain-derived neutrophic factor (BDNF) modulates both the endogenous opioid and noradrenergic systems, we have now studied specific changes in BDNF gene expression related to the maintenance of neuropathic pain in the three rat strains. F344 rats were found to be the only strain that completely recovered from neuropathic pain (mechanical allodynia) 28 days after chronic constriction injury (CCI) of the sciatic nerve.

Morphine and yohimbine regulate midkine gene expression in the rat hippocampus.

Pleiotrophin and midkine are two recently discovered growth factors that promote survival and differentiation of catecholaminergic neurons. Chronic opioid stimulation has been reported to induce marked alterations of the locus coeruleus-hippocampus noradrenergic pathway, an effect that is prevented when opioids are coadministered with the alpha2-adrenoceptor antagonist yohimbine. The present work tries to examine a possible link between yohimbine reversal of morphine effects and pleiotrophin/midkine activation in the rat hippocampus by studying the levels of expression of pleiotrophin and midkine in response to acute and chronic administration of morphine, yohimbine and combinations of both drugs.

Yohimbine prevents morphine-induced changes of glial fibrillary acidic protein in brainstem and alpha2-adrenoceptor gene expression in hippocampus.

The alpha(2)-adrenoceptor antagonist yohimbine is known to oppose to several pharmacological effects of opioid drugs, but the consequences and the mechanisms involved remain to be clearly established. In the present study we have checked the effects of yohimbine on morphine-induced alterations of the expression of key proteins (glial fibrillary acidic protein, GFAP) and genes (alpha(2)-adrenoceptors) in rat brain areas known to be relevant in opioid dependence, addiction and individual vulnerability to drug abuse. Rats were treated with morphine in the presence or absence of yohimbine.

Midkine is a potent regulator of the catecholamine biosynthesis pathway in mouse aorta.

To discover regulatory pathways dependent on midkine (Mk the gene, MK the protein) signaling, we compared the transcriptional profiles of aortae obtained from Mk -/- and wild type (WT, +/+) mice; the comparison demonstrated an extraordinary high level expression of tyrosine hydroxylase (12-fold), the rate-limiting enzyme in catecholamine biosynthesis, DOPA decarboxylase (73-fold), and dopamine beta-hydroxylase (75-fold) in aortae of Mk -/- mice compared with aortae of WT (+/+) mice. Phenylethanolamine-N-methyltransferase, the enzyme catalyzing the conversion of norepinephrine into epinephrine, was not detected in either Mk -/- and WT (+/+) mouse aorta. The protein levels of tyrosine hydroxylase, DOPA decarboxylase and dopamine beta-hydroxylase confirmed the analysis of the transcriptional profiles.

Identification of the angiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch.

Neoplasms progress through genetic and epigenetic mutations that deregulate pathways in the malignant cell that stimulate more aggressive growth of the malignant cell itself and/or remodel the tumor microenvironment to support the developing tumor mass. The appearance of new blood vessels in malignant tumors is known as the "angiogenic switch." The angiogenic switch triggers a stage of rapid tumor growth supported by extensive tumor angiogenesis and a more aggressive tumor phenotype and its onset is a poor prognostic indicator for host survival.

Lewis and Fischer 344 strain differences in alpha2-adrenoceptors and tyrosine hydroxylase expression.

Lewis and Fischer 344 (F344) rats differ in their pharmacological responses to a variety of drugs such as opioids, which has been partially attributed to differences in the endogenous opioid tone. Since opioid and alpha2-adrenergic mechanisms closely interact in nociception and substance abuse, a comparative study of the endogenous alpha2-adrenergic system in both inbred strains is of interest. Alpha-2 adrenoceptor subtypes and tyrosine hydroxylase, the rate-limiting enzyme of the catecholamine biosynthesis, were studied by Taqman RT-PCR analysis of gene expression in four brain areas of F344 and Lewis rats: hypothalamus, hippocampus, striatum and cortex.

Pleiotrophin regulates serine phosphorylation and the cellular distribution of beta-adducin through activation of protein kinase C.

Pleiotrophin (PTN) was found to regulate tyrosine phosphorylation of beta-adducin through the PTN/receptor protein tyrosine phosphatase (RPTP)beta/zeta 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 beta-adducin through activation of either PKC alpha or beta. We also demonstrate that PTN stimulates translocation of phosphoserine 713 and 726 beta-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.

Pleiotrophin stimulates tyrosine phosphorylation of beta-adducin through inactivation of the transmembrane receptor protein tyrosine phosphatase beta/zeta.

Pleiotrophin (PTN the protein, Ptn the gene) signals through a unique mechanism; it inactivates the tyrosine phosphatase activity of its receptor, the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta, and increases tyrosine phosphorylation of the substrates of RPTPbeta/zeta through the continued activity of a yet to be described protein tyrosine kinase(s) in PTN-stimulated cells. We have now found that the cytoskeletal protein beta-adducin interacts with the intracellular domain of RPTPbeta/zeta in a yeast two-hybrid system, that beta-adducin is a substrate of RPTPbeta/zeta, that beta-adducin is phosphorylated in tyrosine in cells not stimulated by PTN, and that tyrosine phosphorylation of beta-adducin is sharply increased in PTN-stimulated cells, suggesting that beta-adducin is a downstream target of and regulated by the PTN/RPTPbeta/zeta signaling pathway. beta-Catenin was the first downstream target of the PTN/RPTPbeta/zeta signaling pathway to be identified; these data thus also suggest that PTN coordinately regulates steady state levels of tyrosine phosphorylation of the important cytoskeletal proteins beta-adducin and beta-catenin and, through PTN-stimulated tyrosine phosphorylation, beta-adducin may contribute to the disruption of cytoskeletal structure, increased plasticity, and loss of homophilic cell-cell adhesion that are the consequences of PTN stimulation of cells and a characteristic feature of different malignant cells with mutations that activate constitutive expression of the endogenous Ptn gene.

Midkine regulates pleiotrophin organ-specific gene expression: evidence for transcriptional regulation and functional redundancy within the pleiotrophin/midkine developmental gene family.

Midkine (MK) and the highly related cytokine pleiotrophin (PTN) constitute the PTN/MK developmental gene family. The Mk and Ptn genes are essential for normal development of the catecholamine and renin-angiotensin pathways and the synthesis of different collagens. It is not known whether the Ptn and Mk genes regulate each other or whether PTN and MK are functionally redundant in development.

Midkine, a newly discovered regulator of the renin-angiotensin pathway in mouse aorta: significance of the pleiotrophin/midkine developmental gene family in angiotensin II signaling.

We previously demonstrated that pleiotrophin (PTN the protein, Ptn the gene) highly regulates the levels of expression of the genes encoding the proteins of the renin-angiotensin pathway in mouse aorta. We now demonstrate that the levels of expression of these same genes are significantly regulated in mouse aorta by the PTN family member midkine (MK the protein, Mk the gene); a 3-fold increase in expression of renin, an 82-fold increase in angiotensinogen, a 6-fold decrease in the angiotensin converting enzyme, and a 6.5-fold increase in the angiotensin II type 1 and a 9-fold increase in the angiotensin II type 2 receptor mRNAs were found in Mk-/- mouse aorta in comparison with the wild type (WT, +/+).

Pleiotrophin induces formation of functional neovasculature in vivo.

Pleiotrophin (PTN) is a heparin-binding growth/differentiation inducing cytokine that shares 50% amino acid sequence identity and striking domain homology with Midkine (MK), the only other member of the Ptn/Mk developmental gene family. The Ptn gene is expressed in sites of early vascular development in embryos and in healing wounds and its constitutive expression in many human tumors is associated with an angiogenic phenotype, suggesting that PTN has an important role in angiogenesis during development and in wound repair and advanced malignancies. To directly test whether PTN is angiogenic in vivo, we injected a plasmid to express PTN into ischemic myocardium in rats.

Fyn is a downstream target of the pleiotrophin/receptor protein tyrosine phosphatase beta/zeta-signaling pathway: regulation of tyrosine phosphorylation of Fyn by pleiotrophin.

Pleiotrophin (PTN the protein, Ptn the gene) signals downstream targets through inactivation of its receptor, the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta, disrupting the balanced activity of RPTPbeta/zeta and the activity of a constitutively active tyrosine kinase. As a consequence of the inactivation of RPTPbeta/zeta, PTN stimulates a sharp increase in the levels of tyrosine phosphorylation of the substrates of RPTPbeta/zeta in PTN-stimulated cells. We now report that the Src family member Fyn interacts with the intracellular domain of RPTPbeta/zeta in a yeast two-hybrid system.

Pleiotrophin is an important regulator of the renin-angiotensin system in mouse aorta.

To better understand the phenotype of pleiotrophin (PTN the protein, Ptn the gene) genetically deficient mice (Ptn -/-), we compared the transcriptional profiles of aortae obtained from Ptn -/- and wild type (WT, Ptn +/+) mice using a 14,400 gene microarray chip (Affymetrix) and confirmed the analysis of relevant genes by real time RT-PCR. We found striking alterations in expression levels of different genes of the renin-angiotensin system of Ptn -/- mice relative to WT (Ptn +/+) mice. The mRNA levels of the angiotensin converting enzyme (ACE) were significantly decreased in Ptn -/- mice whereas the mRNA levels of the angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors were significantly increased in Ptn -/- mice when they were compared with mRNA levels in WT (Ptn +/+) mice aortae.

Pleiotrophin is a major regulator of the catecholamine biosynthesis pathway in mouse aorta.

To better understand the phenotype of pleiotrophin (PTN the protein, Ptn the gene) genetically deficient mice (Ptn -/-), we compared the transcriptional profiles of aortae obtained from Ptn -/- and wild type (WT, Ptn +/+) mice using a 14,400 gene microarray chip (Affymetrix) and confirmed the analysis of relevant genes by real time RT-PCR. We identified a dramatic upregulation of expression of tyrosine hydroxylase (TH), DOPA decarboxylase, and dopamine beta-hydroxylase in aortae of Ptn -/- mice in comparison with WT (Ptn +/+) mice. In contrast, transcripts of phenylethanolamine-N-methyltransferase, the enzyme catalyzing the conversion of norepinephrine into epinephrine, were not detected in aortae in either mouse strain.

Regulation of leptin distribution between plasma and cerebrospinal fluid by cholecystokinin receptors.

Cholecystokinin (CCK) is a postprandial hormone that elicits a satiating effect and regulates feeding behaviour. CCK has been shown to enhance the effect of leptin in several experimental paradigms. The goal of this work was to characterize the effect of endogenous CCK on plasma leptin content by using CCK receptor antagonists.

Characterization of the role of endogenous cholecystokinin on the activity of the paraventricular nucleus of the hypothalamus in rats.

Activation of the hypothalamic-pituitary-adrenal axis by fasting seems to involve cholecystokinin (CCK) receptors. This work aims to characterize the role of endogenous CCK in the activity of the paraventricular nucleus (PVN) of the hypothalamus during food withdrawal. We investigated, by c-Fos immunohistochemistry, the effect of CCK1 and CCK2 receptor antagonists (SR-27,897 and L-365,260, respectively) on c-Fos levels expression induced by food deprivation.