Two different phosphonic acid monolayer films for immobilization of bioactive molecules like the protein BMP-2 on titanium surfaces have been prepared. Monolayers of (11-hydroxyundecyl) phosphonic acid and (12-carboxydodecyl)phosphonic acid molecules were produced by a simple dipping process (the T-BAG method). The terminal functional groups on these monolayers were activated (carbonyl diimidazole for hydroxyl groups and N-hydroxysuccinimide for carboxyl groups) to bind amine containing molecules. The reactivity of the surfaces was investigated using trifluoroethylamine hydrochloride and BMP-2. Each step of the surface modification procedure was characterized by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectroscopy (ToF-SIMS).

The cDNAs encoding the human bone morphogenetic proteins BMP-2 and BMP-4 in an eukaryotic expression vector were permanently transferred into the murine mesenchymal progenitor cell line C3H10T1/2. Originally, these cells are known to differentiate into myotubes, adipocytes, and chondrocytes upon the addition of azacytidine. Permanent transfection of genes encoding human BMP-2 and BMP-4 induces differentiation into the osteogenic lineage. The osteogenic differentiation potential of C3H10T1/2 cells is substantiated by histochemical and genetic analyses of marker genes typical or specific for osteogenesis, including the parathyroid hormone receptor, alkaline phosphatase, osteopontin, osteonectin, and osteocalcin. In addition to osteoblast formation, development into adipocytes and chondrocytes is also observed, suggesting that BMP-2 and BMP-4 induce differentiation into three mesenchymal lineages.

ABSTRACT:Imatinib mesylate (GLEEVEC, GLIVEC, formerly STI571) has demonstrated unprecedented efficacy as first-line therapy for treatment for all phases of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. Disposition and biotransformation of imatinib were studied in four male healthy volunteers after a single oral dose of 239 mg of 14 C-labeled imatinib mesylate. Biological fluids were analyzed for total radioactivity, imatinib, and its main metabolite CGP74588. Metabolite patterns were determined by radio-high-performance liquid chromatography with off-line microplate solid scintillation counting and characterized by liquid chromatography-mass spectrometry. Imatinib treatment was well tolerated without serious adverse events. Absorption was rapid (t max 1-2 h) and complete with imatinib as the major radioactive compound in plasma. Maximum plasma concentrations were 0.921 ؎ 0.095 g/ml (mean ؎ S.D., n ‫؍‬ 4) for imatinib and 0.115 ؎ 0.026 g/ml for the pharmacologically active N-desmethyl metabolite (CGP74588). Mean plasma terminal elimination half-lives were 13.5 ؎ 0.9 h for imatinib, 20.6 ؎ 1.7 h for CGP74588, and 57.3 ؎ 12.5 h for 14 C radioactivity. Imatinib was predominantly cleared through oxidative metabolism. Approximately 65 and 9% of total systemic exposure [AUC 0-24 h (area under the concentration time curve) of radioactivity] corresponded to imatinib and CGP74588, respectively. The remaining proportion corresponded mainly to oxidized derivatives of imatinib and CGP74588. Imatinib and its metabolites were excreted predominantly via the biliary-fecal route. Excretion of radioactivity was slow with a mean radiocarbon recovery of 80% within 7 days (67% in feces, 13% in urine). Approximately 28 and 13% of the dose in the excreta corresponded to imatinib and CGP74588, respectively.

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Abnormal accumulation of soluble oligomers of amyloid ␤ (A␤) is believed to cause malfunctioning of neurons in Alzheimer's disease. It has been shown that A␤ oligomers impair synaptic plasticity, thereby altering the ability of the neuron to store information. We examined the underlying cellular mechanism of A␤ oligomer-induced synaptic modifications by using a recently described stable oligomeric A␤ preparation called "A␤ 1-42 globulomer." Synthetically prepared A␤ 1-42 globulomer has been shown to localize to neurons and impairs long-term potentiation (Barghorn et al., 2005). Here, we demonstrate that A␤ 1-42 globulomer does not affect intrinsic neuronal properties, as assessed by measuring input resistance and discharge characteristics, excluding an unspecific alteration of membrane properties. We provide evidence that A␤ 1-42 globulomer, at concentrations as low as 8 nM, specifically suppresses spontaneous synaptic activity resulting from a reduction of vesicular release at terminals of both GABAergic and glutamatergic synapses. EPSCs and IPSCs were primarily unaffected. A detailed search for the precise molecular target of A␤ 1-42 globulomer revealed a specific inhibition of presynaptic P/Q calcium currents, whereas other voltage-activated calcium currents remained unaltered. Because intact P/Q calcium currents are needed for synaptic plasticity, the disruption of such currents by A␤ 1-42 globulomer may cause deficits in cellular mechanisms of information storage in brains of Alzheimer's disease patients. The inhibitory effect of A␤ 1-42 globulomer on synaptic vesicle release could be reversed by roscovitine, a specific enhancer of P/Q currents. Selective enhancement of the P/Q calcium current may provide a promising strategy in the treatment of Alzheimer's disease.

Tendons and ligaments are elastic collagenous tissues with similar composition and hierarchical structure, contributing to motion. Their strength is related to the number and size of the collagen fibrils. Collagen fibrils increase in size during development and in response to increased physical demands or training. Tendon disorders are commonly seen in clinical practice and give rise to significant morbidity. Treatment is difficult and patients often suffer from the symptoms for quite a long time. Despite remodelling, the biochemical and mechanical properties of healed tendon tissue never match those of intact tendon. The prerequisite for focussed treatment strategies in the future will be an improved understanding of the molecular events both in the embryo and contributing to regeneration in the adult organism. Novel approaches include the local delivery of growth factors, stem-and tendon-cell-derived therapy, the application of mechanical load and gene-therapeutic approaches based on vehicles encoding selected factors, or combinations of these. Important factors are proteins of the extracellular matrix like the metalloproteinases, growth factors like the bone morphogenetic proteins but also intracellular signalling mediator proteins, such as the Smads and transcription factors from the helix-loop-helix and other families. In this review, we focus specifically on such molecular approaches based on mesenchymal stem cells.Résumé Les tendons et les ligaments sont constitués de fibres élastiques de collagène dont la composition est similaire de même que leur structure contribuant au mouvement. Leur résistance est parallèle au nombre et à la taille des fibres collagènes. Si les fibres collagènes grossissent durant la croissance, il en est de même en réponse à une augmentation de l'entraînement physique. A titre clinique on rencontre relativement fréquemment les problèmes tendineux responsables d'une certaine morbidité. Le traitement en est difficile, les patients sont affectés sur un temps relativement long de troubles secondaires à ces lésions. En dépit du remodelage, les propriétés biomécani-ques et biochimiques d'un tendon, d'un tissu tendineux guéri ne peuvent être comparés à ceux d'un tendon sain. Les prérequis d'une stratégie thérapeutique devrait, dans le futur, permettre de mieux comprendre ce qui se passe au moment du développement embryologique et de la régén-ération au niveau de l'organisme adulte. Une nouvelle approche thérapeutique doit prendre en compte l'administration de facteurs de croissance et l'utilisation de cellules souche dans le cadre d'une thérapie génique. Les facteurs importants sont les protéines de la matrice extracellulaire comme les métalloprotéinases de même que les facteurs de croissance de type BMP mais il faut prendre en compte également les facteurs de transcriptions chromosomiques. Pour cette étude, nous nous sommes spécialement centrés sur de telles molécules et sur les cellules souches mesenchymenteuses. Structure and composition of tendons and ligaments

Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytrypatmine 2A receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved. Dopamine and serotonin, as opposed to emerging interest in glutamate, played a dominant role during the formative years of modern psychopharmacology when thinking about the pathophysiology and treatment of schizophrenia. Models derived from studying the behavioral effects of amphetamine and serotonergic hallucinogens were emphasized (Table 1). The seminal observations by Arvid Carlsson and his colleagues in the late early 1960s that first postulated functional dopamine receptor blockade as a necessary therapeutic action by the phenothiazine and butyrophenone structural classes set the stage for our current mechanistic understanding of all antipsychotic drugs currently used today (Carlsson and Lindqvist, 1963). The emergence of in vitro receptor binding and positron emission topography receptor occupancy studies in healthy volunteers and patients identified dopamine D2 receptor Article, publication date, and citation information can be found at

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