Genetic background of type I protein C deficiency in Finland

In contrast to other populations the usually rare type II form of protein C deficiency is as common in Finland as type I deficiency. We recently reported that a single mutation explained virtually all cases of type II protein C deficiency in Finland, indicating strong founder effect. We now investigated in the same population the genetic background of type I protein C deficiency. Thirty-eight apparently unrelated families were studied. They represent the vast majority of all families with type I deficiency in Finland. A genetic defect was identified in 23 (61%) families who carried 13 different mutations. Only three of the 13 mutations have been reported in other populations. Unlike in type II deficiency, considerable heterogeneity in mutations was found in type I deficiency. Our results indicate interesting differences in mutational histories of these two different forms of protein C deficiency in Finland.     

Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine

Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-d-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63–40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5–10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63–10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days?7–11) was reversed by CDPPB or ADX47273 in adults at week?8. This phencyclidine-induced impairment in cognition emerged in adult rats from week?7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks?5–6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week?13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.     

In Vitro Digestion of the Self-Emulsifying Lipid Excipient Labrasol® by Gastrointestinal Lipases and Influence of its Colloidal Structure on Lipolysis Rate

Pharmaceutical Research - Labrasol® is a self-emulsifying excipient used to improve the oral bioavailability of poorly water-soluble drugs. It is a mixture of acylglycerols and PEG esters,...     

ÉquiNanos: innovative team for nanoparticle risk management

Interactions between nanoparticles (NP), humans and the environment are not fully understood yet. Moreover, frameworks aiming at protecting human health have not been adapted to NP but are nonetheless applied to NP-related activities. Consequently, business organizations currently have to deal with NP-related risks despite the lack of a proven effective method of risk-management. To respond to these concerns and fulfill the needs of populations and industries, ÉquiNanos was created as a largely interdisciplinary provincial research team in Canada. ÉquiNanos consists of eight platforms with different areas of action, from adaptive decision-aid tool to public and legal governance, while including biological monitoring. ÉquiNanos resources aim at responding to the concerns of the Quebec nanotechnology industry and public health authorities. Our mandate is to understand the impact of NP on human health in order to protect the population against all potential risks emerging from these high-priority and rapidly expanding innovative technologies.From the Clinical EditorIn this paper by Canadian authors an important framework is discussed with the goal of acquiring more detailed information and establishing an infrastructure to evaluate the interaction between nanoparticles and living organisms, with the ultimate goal of safety and risk management of the rapidly growing fields of nanotechnology-based biological applications.     

Inhibition by SR 59119A of isoprenaline-, forskolin- and VIP-induced relaxation of human isolated bronchi

In the human isolated bronchus (HIB) it has been shown that beta(3)-adrenoceptor stimulation fails to induce relaxation of airway smooth muscle. It has however been reported in human ventricular endomyocardial biopsies that beta(3)-adrenoceptor stimulation induced a marked negative inotropic effect which could be linked to Gi protein activation. The aims of this study were: (1) to determine in HIB (internal diameter 1-2 mm) whether the selective beta(3)-adrenoceptor agonist SR 59119A (N[7-methoxy-1,2,3, 4-tetrahydronaphthalen-(2R)methyl]-(2R)-2-hydroxy-2-(3-chloroph eny l)e thanamine hydrochloride) was able to inhibit adenylate-cyclase-mediated airway smooth muscle relaxation induced by isoprenaline, forskolin or vasoactive intestinal peptide (VIP) and (2) to investigate the role of the Gi protein in this interaction. SR 59119A (0.1 microM and 1 microM) induced a shift to the right of concentration response curve for isoprenaline (-0. 15+/-0.06 and -0.54+/-0.21 log unit, P<0.05 and P<0.01 respectively), forskolin (-0.12+/-0.02 and -0.30+/-0.05 log unit, P<0.001), and VIP (-0.42+/-0.12 log unit, P<0.01 with SR59119A 10(-6)M). The inhibitory effect of SR 59119A was (1) abolished by an incubation of HIB with pertussis toxin (1 microg/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to inactivate the Gi protein and (2) increased after an incubation of HIB with the pro-inflammatory cytokine IL-1beta (10 ng/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to up-regulate Gi protein expression. Our results suggest that the selective beta(3)-adrenoceptor agonist SR59119A might inhibit the cAMP-dependent relaxation of human isolated bronchus through Gi protein-mediated inhibition of adenylate cyclase.     

Formation of ZrC–SiC Composites from the Molecular Scale through the Synthesis of Multielement Polymers

In the field of non-oxide ceramic composites, and by using the polymer-derived ceramic route, understanding the relationship between the thermal behaviour of the preceramic polymers and their structure, leading to the mechanisms involved, is crucial. To investigate the role of Zr on the fabrication of ZrC–SiC composites, linear or hyperbranched polycarbosilanes and polyzirconocarbosilanes were synthesised through either “click-chemistry” or hydrosilylation reactions. Then, the thermal behaviours of these polymeric structures were considered, notably to understand the impact of Zr on the thermal path going to the composites. The inorganic materials were characterised by thermogravimetry-mass spectrometry (TG-MS), X-ray diffraction (XRD), and scanning electron microscopy (SEM). To link the macromolecular structure to the organisation involved during the ceramisation process, eight temperature domains were highlighted on the TG analyses, and a four-step mechanism was proposed for the polymers synthesised by a hydrosilylation reaction, as they displayed better ceramic yields. Globally, the introduction of Zr in the polymer had several effects on the temperature fragmentation mechanisms of the organometallic polymeric structures: (i) instead of stepwise mass losses, continuous fragment release prevailed; (ii) the stability of preceramic polymers was impacted, with relatively good ceramic yields; (iii) it modulated the chemical composition of the generated composites as it led, inter alia, to the consumption of free carbon.