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.     

The influence of drug use in university hospitals on the pharmaceutical consumption in their surrounding communities

Aim

To investigate the influence of hospital drug choices on pharmaceutical consumption for nine competitive classes in the surrounding community.

Methods

Ecological study. Data from the national survey on drugs in hospitals were used to extract quantities purchased by 25 French university hospitals for three ‘hospital classes’ (EPOs, LMWHs and setrons) and six ‘ambulatory classes’ (PPIs, ACEIs and ARBs, statins, α-adrenoreceptor antagonists (AAAs) and selective serotonin re-uptake inhibitors SSRIs). Re-imbursed quantities for patients living in the hospital''s catchment area were extracted from the national health insurance database. The relationship between the use of a brand in hospitals and their catchment areas was assessed using multivariate linear regressions with instrumental variables.

Results

An increase of 1 day of treatment with one brand in the hospital was associated with a significant increase of 2.8 days of treatment with the same brand in the catchment area. However, results strongly varied according to classes. An increase of 1 day of treatment in the hospital was significantly associated with an increase of 0.21 day for ‘hospital classes’ and 21.8 days for ‘ambulatory classes’ in the catchment area. Strong variations were seen across ‘ambulatory classes’. The effect was maximal for cardiovascular classes and not significant for AAAs and SSRIs. The size of the effect also varied with hospital characteristics: small and proximity university hospitals exerted the greatest influence.

Conclusions

Hospital consumption influences the use of drugs in the community. A significant effect was found, especially for competitive classes used on a long-term basis. The economic consequences of these findings need to be addressed.     

Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: A case study with acetaminophen

In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only ‘as a last resort’ or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on in vitro tests and QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose–response model predicting hepatotoxicity. The dose response consists in calibrating and coupling a PBPK (physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods.     

Solid-Solid Transformation in Racemic Ibuprofen

Purpose

To clarify the polymorphism of racemic Ibuprofen and to determine the kinetic of the phase transformation that follows crystallisation of phase II.

Methods

Differential Scanning Calorimetry (DSC), X-ray powder diffraction and Hot Stage Microscopy are complementarily used to perform a kinetic investigation of the particular temperature range where competition between the occurrence of phases I and II is suspected.

Results

Experiments performed with the three techniques reveal that at 273?K the crystallisation to phase II is then followed by a solid-solid transition towards phase I. This transformation is exothermic (conversion enthalpy of 8.0?±?0.5?kJ/mol), which proves that the two phases form a monotropic set. The kinetics of conversion deduced from X-Ray experiments follows a Johnson-Mehl-Avrami equation and the Hot Stage Microscopy allows us to establish that the transformation proceeds by the growth of some nuclei of phase I probably formed at lower temperature.

Conclusions

These results allow us to precise the stability pattern of racemic Ibuprofen and to establish the kinetic conditions of appearance and interconversion of the different phases. Therefore such real time resolved investigations would help if applied in the screening of polymorphs when competitive crystallisations occur.     

Preceptor questioning and student critical thinking.

Questioning is fundamental to student learning. Not only does it enable students to elevate their level of thinking, but in the process it also affords them the opportunity to deal with their world intelligently. The practice setting is an environment rich in opportunity for enabling critical thinking through the use of questioning. In the preceptorship experience, preceptors are in a prime position to use questioning behaviors that can challenge the way preceptees think, encourage them to justify or clarify their assertions, promote the generation of original ideas, explanations, or solutions to patient problems, provide mental and emotional tools to help resolve dilemmas, promote discussion, and evaluate learning. This article discusses the importance of preceptor questioning for the development and promotion of student critical thinking. Contextually, the authors draw on the findings of a recent study in which preceptor questioning of the knowledge base, decision making, and actions of the preceptee were found to directly bring about or trigger their critical thinking. This article allows for some further reflection on that process and its contribution to the enhancement of the preceptorship experience.     

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.     

The levels of anti-HPV16/18 and anti-HPV31/33/35/45/52/58 antibodies among AS04-adjuvanted HPV16/18 vaccinated and non-vaccinated Ugandan girls aged 10–16 years

Background

Data on Human Papilloma virus (HPV) vaccine immune response in sub-Saharan Africa is still sparse yet such knowledge is critical for optimal implementation and monitoring of HPV vaccines. Our primary objective was to evaluate levels of anti-HPV-16/18 antibodies and six other ‘high risk’ HPV (hrHPV) types among the vaccinated and unvaccinated Ugandan girls.

Methods

We conducted a cross sectional study among AS04-adjuvanted HPV-16/18 vaccinated and unvaccinated school girls aged 10–16 years in Western Uganda using purposive sampling. The vaccinated girls were at 18 months post vaccination. After consenting and assenting, data was collected using interviewer administered questionnaires for demographics and sexual history. Blood was drawn from which serum samples were analysed by the multiplex HPV serology technology to determine anti-HPV antibody levels to HPV-16/18 and six other hrHPV types (31, 33, 35, 45, 52 and 58). The antibody levels were expressed as Median Fluorescent Intensity (MFI).A total of 207 vaccinated [mean age 13.1 years (SD 1.5); range 10-16 years] and 197 unvaccinated girls [mean age 13.6 years (SD 1.3); range 10-16 years] participated in the study. Sexual activity was self reported among 14/207 (6.8%) vaccinated and 5/197 (2.5%) unvaccinated girls. The MFI levels for HPV-16 and HPV-18 were 15 and 20 times higher respectively in the vaccinated girls than in the unvaccinated girls. HPV-16 mean MFI level was 4691(SD 1812; 95% CI: 4438-4958) among the vaccinated compared to 218 (SD 685; 95% CI: 190-252) among the unvaccinated girls. For HPV-18 the mean MFI level was 1615 (SD 1326; 95% CI: 1470-1776) among the vaccinated compared to MFI 103 (SD 506; 95% CI: 88 -121) among unvaccinated girls.In addition antibody levels to non vaccine hrHPV types (31, 33, 35, 45, 52 and 58) were all significantly higher in the vaccinated group than in the unvaccinated group (p<0.01).

Conclusion

The AS04-Adjuvanted HPV-16/18 vaccinated girls showed a higher level of antibodies to HPV-16/18 and other non-vaccine hrHPV types compared to the unvaccinated girls. This may translate into protection against HPV-16/18 and other hrHPV types.

     

Triple negative tumors accumulate significantly less methylglyoxal specific adducts than other human breast cancer subtypes

Metabolic syndrome and type 2 diabetes are associated with increased risk of breast cancer development and progression. Methylglyoxal (MG), a glycolysis by-product, is generated through a non-enzymatic reaction from triose-phosphate intermediates. This dicarbonyl compound is highly reactive and contributes to the accumulation of advanced glycation end products. In this study, we analyzed the accumulation of Arg-pyrimidine, a MG-arginine adduct, in human breast adenocarcinoma and we observed a consistent increase of Arg-pyrimidine in cancer cells when compared with the non-tumoral counterpart. Further immunohistochemical comparative analysis of breast cancer subtypes revealed that triple negative lesions exhibited low accumulation of Arg-pyrimidine compared with other subtypes. Interestingly, the activity of glyoxalase 1 (Glo-1), an enzyme that detoxifies MG, was significantly higher in triple negative than in other subtype lesions, suggesting that these aggressive tumors are able to develop an efficient response against dicarbonyl stress. Using breast cancer cell lines, we substantiated these clinical observations by showing that, in contrast to triple positive, triple negative cells induced Glo-1 expression and activity in response to MG treatment. This is the first report that Arg-pyrimidine adduct accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes.