Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to α-Hexabromocyclododecane.

Assessing the role of α-hexabromocyclododecane α-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of α-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to α-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to α-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of α-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. α-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate α-HBCDD co-exposure.

New injectable self-assembled hydrogels that promote angiogenesis through a bioactive degradation product.

Hydrogels used in regenerative medicine are often designed to allow cellular infiltration, degradation, and neovascularization. Low molecular weight hydrogels (LMWHs), formed by self-assembly via non-covalent interactions, are gaining significant interest because they are soft, easy to use and injectable. We propose LMWHs as suitable body implant materials that can stimulate tissue regeneration. We produced four new LMWHs with molecular entities containing nucleic acid and lipid building blocks and analyzed the foreign body response upon subcutaneous implantation into mice. Despite being infiltrated with macrophages, none of the hydrogels triggered detrimental inflammatory responses. Most macrophages present in the hydrogel-surrounding tissue acquired an immuno-modulatory rather than inflammatory phenotype. Concomitantly, no fibrotic capsule was formed after three weeks. Our glyconucleolipid LMWHs exhibited different degradation kinetics in vivo and in vitro. LMWHs with high angiogenic properties in vivo, were found to release glyconucleoside (glucose covalently linked to thymidine via a triazole moiety) as a common by-product of in vitro LMWH degradation. Chemically synthesized glyconucleoside exhibited angiogenic properties in vitro in scratch assays with monolayers of human endothelial cells and in vivo using the chick chorioallantoic membrane assay. Collectively, LMWHs hold promise as efficient scaffolds for various regenerative applications by displaying good biointegration without causing fibrosis, and by promoting angiogenesis through the release of a pro-angiogenic degradation product. STATEMENT OF SIGNIFICANCE: The main limitations of biomaterials developed in the field of tissue engineering remains their biocompatibility and vascularisation properties. In this context, we developed injectable Low Molecular Weight Hydrogels (LMWH) exhibiting thixotropic (reversible gelation) and thermal reversible properties. LMWH having injectability is of great advantage since it allows for their delivery without wounding the surrounding tissues. The resulting gels aim at forming scaffolds that the host cells colonize without major inflammation, and that won't be insulated by a strong fibrosis reaction. Importantly, their molecular degradation releases a product (a glycosyl-nucleoside conjugate) promoting angiogenesis. In this sense, these LMWH represent an important advance in the development of biomaterials promoting tissue regeneration.

Learning from our mistakes: using key opportunities to remove the perverse incentives that help drive antibiotic resistance.

Introduction: Governments need to do far more to help curb the emergence and transmission of antibiotic resistance and help protect the efficacy of any new antibiotics that come to the market. Industry is an important stakeholder that must be brought on-board such efforts given its influence on the direction and scale of antibiotic sales. Financial incentives supporting industry R&D of novel antibiotics should structurally remove the drivers of superfluous sales and encourage access to newer antibiotics where infections are otherwise resistant to treatment. Indeed, the use of public money provides an important opportunity to prioritize these public health goals within market structures such that we both adequately reward industry for their efforts and prolong antibiotic efficacy for as long as possible.Areas covered: This work discusses possible financial 'pull' incentives that fully delink the reward paid to the developer from unit sales, examining their primary advantages and limitations.Expert opinion: Pharmaceutical companies need to be rewarded generously for their efforts to develop new, badly needed antibiotics. But the current marketplace does not provide a sustained financial lure and its reliance on unit-sales for profitability jeopardizes the efficacy of antibiotics both new and old. Fully delinked models can make antibiotic R&D more financially appealing and create a market environment that is far less threatening to public health.

Multidisciplinary team meeting and EUSOMA quality indicators in breast cancer care: A French regional multicenter study.

INTRODUCTION: We evaluate breast cancer (BC) pathway at a regional level including public, private and university institutions. We assessed the quality of multidisciplinary team meetings (MTM) and compliance with a panel of European high-quality indicators (EUSOMA QIs). METHODS: We conducted a retrospective multicenter (n = 20) study in the largest health care region in France. Between January and April 2015, we included all patients discussed at an MTM after a diagnosis of BC (n = 619). We analyzed quality of MTM by assessing the quorum, the reliability of data transcription and the exhaustivity of pre-therapeutic MTM. We then analyzed the compliance with a selected panel of 16 EUSOMA QIs. RESULTS: During MTM discussion, data were more than 95% consistent with medical records for 9/11 items. Pre-operative tumor histology (90.6%) and post-operative resection margins (84.3%) were the least concordant between medical records and MTM. Minimum standards as defined by EUSOMA were reached for 11/16 QIs, but not reached for pathology reports in non-invasive BC (78.2%), proportion of exclusive sentinel lymph node biopsies in patients with clinically negative axilla (85.2%), performing adjuvant chemotherapy (76.6%), and proportion of patients discussed in pre-therapeutic and post-operative MTM (63.5%). CONCLUSIONS: In this multicentric study evaluating the quality of BC care with a representative sample of institutions, compliance with EUSOMA indicators was satisfactory for all type of institutions. However, too few patients were discussed in pre-therapeutic MTM (especially in non-university hospitals 43.7% [39.4-48.1]) versus 88.7% for others [82.2-95.1]) and data transcription was likely responsible for up to 15% of discordance.

Non-contrast magnetic resonance imaging for monitoring patients with acoustic neuroma.

OBJECTIVE: To assess the feasibility of non-contrast T2-weighted magnetic resonance imaging as compared to T1-weighted post-contrast magnetic resonance imaging for detecting acoustic neuroma growth. METHODS: Adult patients with acoustic neuroma who underwent at least three magnetic resonance imaging scans of the internal auditory canals with and without contrast in the past nine years were identified. T1- and T2-weighted images were reviewed by three neuroradiologists, and tumour size was measured. Accuracy of the measurements on T2-weighted images was defined as a difference of less than or equal to 2 mm from the measurement on T1-weighted images. RESULTS: A total of 107 magnetic resonance imaging scans of 26 patients were reviewed. Measurements on T2-weighted magnetic resonance imaging scans were 88 per cent accurate. Measurements on T2-weighted images differed from measurements on T1-weighted images by an average of 1.27 mm, or 10.4 per cent of the total size. The specificity of T2-weighted images was 88.2 per cent and the sensitivity was 77.8 per cent. CONCLUSION: The T2-weighted sequences are fairly accurate in measuring acoustic neuroma size and identifying growth if one keeps in mind the caveats associated with the tumour characteristics or location.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells' activity.

Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking ß2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.

Preserving the 'commons': addressing the sustainable use of antibiotics through an economic lens.

BACKGROUND: As the growth of antibiotic resistance has resulted in large part from widespread use of antibiotics, every effort must be made to ensure their sustainable use. AIMS: This narrative review aims to assess the potential contribution of health economic analyses to sustainable use efforts. SOURCES: The work draws on existing literature and experience with health economic tools. CONTENT: The study examines some of the weaknesses in the health, regulatory, and industry arenas that could contribute to inappropriate or suboptimal prescribing of antibiotics and describes how economic analysis could be used to improve current practice by comparing both costs and health outcomes to maximize societal wellbeing over the longer-term. It finds that economic considerations underpinning current antibiotic prescribing strategies are incomplete and short-termist, with the result that they may foster suboptimal use. It also stresses that perverse incentives that drive antibiotic sales and inappropriate prescribing practices must be dis-entangled for sustainable use policies to gain traction. Finally, payment structures can be used to re-align incentives and promote optimal prescribing and sustainable use more generally. In particular, eliminating or altering reimbursement differentials could help steer clinical practice more deliberately towards the minimization of selection pressure and the resulting levels of antibiotic resistance. IMPLICATIONS: This work highlights the need for appropriately designed cost-effectiveness analyses, incentives analysis, and novel remuneration systems to underpin sustainable use policies both within and beyond the health sector.

[Eosinophilic esophagitis in children: Evaluation of practices through a multicenter study]. / L'œsophagite à éosinophiles chez l'enfant : évaluation des pratiques.

Eosinophilic esophagitis (EE) is a recent pathology defined by abnormal immune response of the esophageal mucosa to exogenous allergens, leading to chronic mucosa infiltration by 15 eosinophils per High-Power-Field (Eos/HPF). The present retrospective study was designed to assess the hospital care for children suffering from EE in several hospitals in western France in order to highlight discrepancies and improve future care. Twenty-eight children ranging from 1.5 months to 17 years old were included in the study. Episodes of food blockage were the most frequently reported symptoms (46 %). A ratio of 29 % of EE patients reported macroscopically normal endoscopy; diagnosis was then established upon histological anomalies found in biopsies. The mean eosinophil count was 72.4 Eos/HPF. Centralized immunohistochemical staining revealed the presence of IgG4-responding plasma cells in 76.5 % of patients, as well as IgG4 intraepithelial degranulation in 14 % of them. The evaluation of the treatment plan showed important inter-center discrepancies with only 43 % of patients receiving endoscopic reevaluation. This study objectively highlights heterogeneities in diagnosis and care provided to children suffering from EE. Therefore, improving the consistency of practices seems to be crucial to optimize the patients' outcome. The role of IgG4 as a new diagnosis marker remains to be clarified.

Comparing the cost-effectiveness of linezolid to trimethoprim/sulfamethoxazole plus rifampicin for the treatment of methicillin-resistant Staphylococcus aureus infection: a healthcare system perspective.

OBJECTIVE: Few industry-independent studies have been conducted to compare the relative costs and benefits of drugs to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. We performed a stochastic cost-effectiveness analysis comparing two treatment strategies-linezolid versus trimethoprim-sulfamethoxazole plus rifampicin-for the treatment of MRSA infection. METHODS: We used cost and effectiveness data from a previously conducted clinical trial, complementing with other data from published literature, to compare the two regimens from a healthcare system perspective. Effectiveness was expressed in terms of quality-adjusted life-years (QALYs). Several sensitivity analyses were performed using Monte Carlo simulation, to measure the effect of potential parameter changes on the base-case model results, including potential differences related to type of infection and drug toxicity. RESULTS: Treatment of MRSA infection with trimethoprim-sulfamethoxazole plus rifampicin and linezolid were found to cost on average €146 and €2536, and lead to a gain of 0.916 and 0.881 QALYs, respectively. Treatment with trimethoprim-sulfamethoxazole plus rifampicin was found to be more cost-effective than linezolid in the base case and remained dominant over linezolid in most alternative scenarios, including different types of MRSA infection and potential disadvantages in terms of toxicity. With a willingness-to-pay threshold of €0, €50 000 and €200 000 per QALY gained, trimethoprim-sulfamethoxazole plus rifampicin was dominant in 100%, 96% and 85% of model iterations. A 95% discount on the current purchasing price of linezolid would be needed when it goes off-patent for it to represent better value for money compared with trimethoprim-sulfamethoxazole plus rifampicin. CONCLUSIONS: Combined treatment of trimethoprim-sulfamethoxazole plus rifampicin is more cost-effective than linezolid in the treatment of MRSA infection.

[Treatment of age-related macular degeneration: Expert opinion and therapeutic algorithm]. / Traitement de la dégénérescence maculaire liée à l'âge : avis d'experts et algorithme thérapeutique.

UNLABELLED: Intravitreal injections (IVT) of aflibercept are indicated in France for the treatment of neovascular age-related macular degeneration (AMD). An induction phase consisting of 3 monthly IVTs followed by follow-up visits and IVTs every other month during the first year is recommended. However, it may be necessary to adjust this schedule for some patients who might benefit from a more tailored approach, namely a follow-up visit immediately after the induction phase. The goal was to develop a treatment algorithm that would reflect current clinical experience and the opinions of experts on neovascular AMD. METHODS: A group of retinologists took positions on therapeutic questions regarding management of AMD using a nominal group technique (NGT). The results were combined to create a treatment algorithm. RESULTS: Seventy-nine percent of experts considered that the approved schedule was efficacious when fluid was completely resorbed after the induction phase. Ninety-four percent of experts recommended, after a successful induction phase, a monthly follow-up visit for 3 to 6 months in order to determine the rhythm of recurrence for each patient. Ninety-six percent of experts recommended that persistent fluid after the induction phase, even if visual acuity is improved satisfactorily, should be a criterion for systematic retreatment. CONCLUSION: The proposed algorithm (expert opinion) after the first year of use of aflibercept in France captures the complexity of the clinical cases that exist in daily practice and the necessity for regular follow-ups.

K-edge imaging with the XPAD3 hybrid pixel detector, direct comparison of CdTe and Si sensors.

We investigate the improvement from the use of high-Z CdTe sensors for pre-clinical K-edge imaging with the hybrid pixel detectors XPAD3. We compare XPAD3 chips bump bonded to Si or CdTe sensors in identical experimental conditions. Image performance for narrow energy bin acquisitions and contrast-to-noise ratios of K-edge images are presented and compared. CdTe sensors achieve signal-to-noise ratios at least three times higher than Si sensors within narrow energy bins, thanks to their much higher detection efficiency. Nevertheless Si sensors provide better contrast-to-noise ratios in K-edge imaging when working at equivalent counting statistics, due to their better estimation of the attenuation coefficient of the contrast agent. Results are compared to simulated data in the case of the XPAD3/Si detector. Good agreement is observed when including charge sharing between pixels, which have a strong impact on contrast-to-noise ratios in K-edge images.

PIXSIC, a pixelated ß⁺-sensitive probe for radiopharmacological investigations in rat brain: binding studies with [¹8F]MPPF.

PURPOSE: The aim of this work was to demonstrate the pharmacokinetic potential of a wireless pixelated ß(+)-sensitive probe (PIXSIC). PROCEDURES: The binding of 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), a 5-HT1A serotonin receptor radiopharmaceutical, was measured in anesthetized rats and compared to microPET data. The effects of a 5-HT1A antagonist injection on in vivo [(18)F]MPPF binding were monitored by PIXSIC. RESULTS: PIXSIC allowed differentiating the radioactive kinetics according to the location of its pixels in the hippocampus, cortex, corpus callosum, and cerebellum. The device accurately detected the changes in [(18)F]MPPF binding, after 5-HT1A antagonist blockade. The time-activity curves were reproducible and consistent with kinetics obtained simultaneously with a microPET camera. CONCLUSIONS: These results demonstrate the ability of the PIXSIC device to record reliably the binding of PET ligands, with a high spatiotemporal resolution in anesthetized rodents. These first in vivo results are a key stage on the path to its implementation in awake freely moving animals.

Nicotine consumption is regulated by a human polymorphism in dopamine neurons.

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and ß4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

A wireless beta-microprobe based on pixelated silicon for in vivo brain studies in freely moving rats.

The investigation of neurophysiological mechanisms underlying the functional specificity of brain regions requires the development of technologies that are well adjusted to in vivo studies in small animals. An exciting challenge remains the combination of brain imaging and behavioural studies, which associates molecular processes of neuronal communications to their related actions. A pixelated intracerebral probe (PIXSIC) presents a novel strategy using a submillimetric probe for beta(+) radiotracer detection based on a pixelated silicon diode that can be stereotaxically implanted in the brain region of interest. This fully autonomous detection system permits time-resolved high sensitivity measurements of radiotracers with additional imaging features in freely moving rats. An application-specific integrated circuit (ASIC) allows for parallel signal processing of each pixel and enables the wireless operation. All components of the detector were tested and characterized. The beta(+) sensitivity of the system was determined with the probe dipped into radiotracer solutions. Monte Carlo simulations served to validate the experimental values and assess the contribution of gamma noise. Preliminary implantation tests on anaesthetized rats proved PIXSIC's functionality in brain tissue. High spatial resolution allows for the visualization of radiotracer concentration in different brain regions with high temporal resolution.

[Peroperative anaphylactic shock in children: management and evaluation]. / Choc anaphylactique peropératoire chez l'enfant : prise en charge et bilan.

Anaphylactic shock is the most severe manifestation of hypersensitivity, whether of allergic origin or not. In the operating theatre, anaphylactic shock is rare in paediatric patients and latex allergy is still the major cause of allergy. Whatever the cause and mechanism of the reaction, its treatment should be started as early as possible: a high level of suspicion is thus necessary to establish a diagnosis as early as possible. Symptomatic treatment is well codified. The results of blood sampling at the time of the reaction and of allergic tests performed a few weeks later will enable a definitive diagnosis to be made and appropriate recommendations (medical alert card) to be given to the patients and its parents.

Identification of genomic deletions spanning the PCDH19 gene in two unrelated girls with intellectual disability and seizures.

Recently, missense and truncating mutations in the gene PCDH19 have been reported to cause female-restricted epilepsy with mental retardation (EFMR). EFMR (MIM#300088) is an X-linked disorder characterized by early onset seizures and intellectual disability (ID). Interestingly, unlike typical X-linked mode of inheritance, the phenotype is restricted to females, and males are unaffected carriers. PCDH19 is highly expressed in brain, and the encoded protein belongs to the cadherin superfamily. Here we report two unrelated female patients with deletions spanning PCDH19 identified by copy number variation (CNV) analysis and validated by qPCR. In one, we have identified a 3 Mb interstitial deletion at Xq21.33-q22.1 which spans PCDH19, LOC442459 & TNMD. This patient had her first seizure at 8 months old, and also has ID and aggressive behavior. In another female patient we identified a de novo 603 kb heterozygous deletion in a female patient with fits (since 1 year of age), ID, hyperactivity and aggressive behavior. The deletion spans the entire PCDH19 gene (also TNMD, SRPX2, TSPAN6 and SYTL4). In conclusion, our results suggest that deletions at PCDH19 also cause EFMR.

Delivery of gelfoam-enabled cells and vectors into the pericardial space using a percutaneous approach in a porcine model.

Intrapericardial drug delivery is a promising procedure, with the ability to localize therapeutics with the heart. Gelfoam particles are nontoxic, inexpensive, nonimmunogenic and biodegradable compounds that can be used to deliver therapeutic agents. We developed a new percutaneous approach method for intrapericardial injection, puncturing the pericardial sac safely under fluoroscopy and intravascular ultrasound (IVUS) guidance. In a porcine model of myocardial infarction (MI), we deployed gelfoam particles carrying either (a) autologous mesenchymal stem cells (MSCs) or (b) an adenovirus encoding enhanced green fluorescent protein (eGFP) 48 h post-MI. The presence of MSCs and viral infection at the infarct zone was confirmed by immunoflourescence and PCR. Puncture was performed successfully in 16 animals. Using IVUS, we successfully determined the size of the pericardial space before the puncture, and safely accessed that space in setting of pericardial effusion and also adhesions induced by the MI. Intrapericardial injection of gelfoam was safe and reliable. Presence of the MSCs and eGFP expression from adenovirus in the myocardium were confirmed after delivery. Our novel percutaneous approach to deliver (stem-) cells or adenovirus was safe and efficient in this pre-clinical model. IVUS-guided delivery is a minimally invasive procedure that seems to be a promising new strategy to deliver therapeutic agents locally to the heart.