0272: Unfractionated heparin addition during percutaneous coronary intervention in acute coronary syndrome patients previously treated with enoxaparin: biological impact

BackgroundThe benefit of anticoagulants (AC) to prevent thrombotic complications during percutaneous coronary intervention (PCI) is well established. In acute coronary syndrome (ACS) patients previously treated with enoxaparin, an additional bolus of AC is not recommended if the last injection was realized within 8 h. In this setting, many interventional cardiologists use unfractionated heparin (UFH) at the time of sheath insertion.ObjectivesThe aim of our study was to describe local current practices for AC use during PCI in patients already treated with enoxaparin and admitted for ACS and to assess the biological impact of UFH addition at the beginning of the procedure.MethodsA standardized survey was sent to the interventional cardiologists of the southwest of France to investigate their practice in terms of periprocedural AC use. In 2 centers, ACS patients previously treated with subcutaneous injection of enoxaparin within 8 h and who received intravenous UFH at the time of sheath insertion were prospectively included and their plasma anti-Xa activity was assessed at the sheath insertion and 30 min after UFH bolus. In-hospital bleeding and ischemic events were collected. The adequate therapeutic window was defined by anti Xa activity (range 0.5 to 0.9 IU/mL). Results: Among the 41 interventional cardiologists who replied, a large majority (75,6%) considered the addition of UFH in patients who received enoxaparin within 8 h as a valid option. 47 ACS patients were enrolled. The dose of the bolus of UFH was highly variable from 20 to 90 UI / kg. Anti-Xa activities were above 0.9 IU/mL in 14,9% of patients at the sheath insertion and in 72,3% of patients 30 min after UFH injection. 2 bleeding complications occurred, both in over-coagulated patients. No ischemic events were reported.ConclusionThe use of UFH in patients who already received enoxaparin may result in over-anticoagulation and lead to bleeding complications

Cathepsin B pH-Dependent Activity Is Involved in Lysosomal Dysregulation in Atrophic Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is characterized by retinal pigment epithelial (RPE) cell dysfunction beginning at early stages of the disease. The lack of an appropriate in vitro model is a major limitation in understanding the mechanisms leading to the occurrence of AMD. This study compared human-induced pluripotent stem cell- (hiPSC-) RPE cells derived from atrophic AMD patients () to hiPSC-RPE cells derived from healthy elderly individuals with no drusen or pigmentary alteration (). Control and AMD hiPSC-RPE cell lines were characterized by immunofluorescence, flow cytometry, and electronic microscopy. The toxicity level of iron after Fe-NTA treatment was evaluated by an MTT test and by the detection of dichloro-dihydro-fluorescein diacetate. Twelve hiPSC-RPE cell lines (6 AMD and 6 controls) were used for the experiment. Under basal conditions, all hiPSC-RPE cells expressed a phenotypic profile of senescent cells with rounded mitochondria at passage 2. However, the treatment with Fe-NTA induced higher reactive oxygen species production and cell death in hiPSC-RPE AMD cells than in hiPSC-RPE Control cells. Interestingly, functional analysis showed differences in lysosomal activity between the two populations. Indeed, Cathepsin B activity was higher in hiPSC-RPE AMD cells compared to hiPSC-RPE Control cells in basal condition and link to a pH more acidic in this cell population. Moreover, oxidative stress exposure leads to an increase of Cathepsin D immature form levels in both populations, but in a higher proportion in hiPSC-RPE AMD cells. These findings could demonstrate that hiPSC-RPE AMD cells have a typical disease phenotype compared to hiPSC-RPE Control cells

Maturité des financements et contrats de partenariats public‑privé : les enjeux du refinancement à mi-parcours

La soutenabilité budgétaire des contrats de partenariat public-privé dépend essentiellement du niveau du loyer annuel qui doit être versé au contractant de l’administration. L’augmentation du niveau des taux d’intérêts et la réduction de la durée moyenne des prêts après la crise financière de 2008 changèrent les conditions de financement des partenariats public-privé. Les coûts financiers additionnels liés à l’élévation des primes de risque peuvent être considérés comme de nature à mettre en cause l’opportunité financière même du recours à de tels contrats. Cependant, l’élévation du surcoût du financement privé n’est pas le seul effet négatif lié à la crise. La difficulté de disposer de financements dont la maturité est équivalente à celle du contrat impose de devoir refinancer ce dernier dans le courant de son exécution. Il en découle un risque additionnel dont on ne peut évaluer le coût potentiel à la signature du contrat. Notre propos dans cette contribution est d’en illustrer les éventuelles conséquences financières tant pour le contractant public que pour le contractant privé. Pour des contrats de courte durée, portant essentiellement sur des missions d’exploitation, une moindre maturité n’a que peu d’effets sur l’efficacité financière. À l’inverse, pour des contrats supposant des montants d’investissements élevés, une autorité publique contractante risquophobe, préfèrera opter pour une architecture contractuelle permettant de transférer à l’opérateur privé la charge de ce risque de refinancement.The affordability of public-private partnership contracts mostly depends on the level of their annual financial charge. Therefore, high interest rates and short duration of the loans can outweigh the savings of bundling design, building and operation in the same contract. In order to match the durations of contract and loan, we assume that a refinancing allows for bridging the gap between the initial loan and the end of the contract. As the future cost of refinancing is unknown when signing the contract, we investigate the value for money of refinancing risk borne either by the private sector or by the purchasing authority. We conclude that in operation intensive public-private partnerships, a shorter contract has little effect on the value for money of the project. Conversely, in capital-intensive projects, a risk-adverse purchasing authority should rather choose contracts transferring the refinancing risk to the private sector

Increased vulnerability of nigral dopamine neurons after expansion of their axonal arborization size through D2 dopamine receptor conditional knockout

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Rare genetic mutations in genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for the disease in about 15% of the cases. A key unanswered question in PD pathophysiology is why would these mutations, impacting basic cellular processes such as mitochondrial function and neurotransmission, lead to selective degeneration of SNc DA neurons? We previously showed in vitro that SNc DA neurons have an extremely high rate of mitochondrial oxidative phosphorylation and ATP production, characteristics that appear to be the result of their highly complex axonal arborization. To test the hypothesis in vivo that axon arborization size is a key determinant of vulnerability, we selectively labeled SNc or VTA DA neurons using floxed YFP viral injections in DAT-cre mice and showed that SNc DA neurons have a much more arborized axon than those of the VTA. To further enhance this difference, which may represent a limiting factor in the basal vulnerability of these neurons, we selectively deleted in mice the DA D2 receptor (D2-cKO), a key negative regulator of the axonal arbour of DA neurons. In these mice, SNc DA neurons have a 2-fold larger axonal arborization, release less DA and are more vulnerable to a 6-OHDA lesion, but not to α-synuclein overexpression when compared to control SNc DA neurons. This work adds to the accumulating evidence that the axonal arborization size of SNc DA neurons plays a key role in their vulnerability in the context of PD

Loss of independence in Katz's ADL ability in connection with an acute hospitalization: early clinical markers in French older people

Background: The preservation of autonomy and the ability of elderly to carry out the basic activities of daily living, beyond the therapeutic care of any pathologies, appears as one of the main objectives of care during hospitalization. Objectives: To identify early clinical markers associated with the loss of independence in elderly people in short stay hospitals. Methods: Among the 1,306 subjects making up the prospective and multicenter SAFEs cohort study (Sujet Agé Fragile: Évolution et suivi—Frail elderly subjects, evaluation and follow-up), 619 medical inpatients, not disabled at baseline and hospitalized through an emergency department were considered. Data used in a multinomial logistic regression were obtained through a comprehensive geriatric assessment (CGA) conducted in the first week of hospitalization. Dependency levels were assessed at baseline, at inclusion and at 30days using Katz's ADL index. Baseline was defined as the dependence level before occurrence of the event motivating hospitalization. To limit the influence of rehabilitation on the level of dependence, only stays shorter than 30days were considered. Results: About 514 patients were eligible, 15 died and 90 were still hospitalized at end point (n=619). Two-thirds of subjects were women, with a mean age of 83. At day 30 162 patients (31%) were not disabled; 61 (12%) were moderately disabled and 291 severely disabled (57%). No socio-demographic variables seemed to influence the day 30 dependence level. Lack of autonomy (odds ratio (OR)=1.9, 95% confidence interval (CI)=1.2-3.6), walking difficulties (OR=2.7, 95% CI=1.3-5.6), fall risk (OR=2.1, 95% CI=1.3-6.8) and malnutrition risk (OR=2.2, 95% CI=1.5-7.6) were found in multifactorial analysis to be clinical markers for loss of independence. Conclusions: Beyond considerations on the designing of preventive policies targeting the populations at risk that have been identified here, the identification of functional factors (lack of autonomy, walking difficulties, risk of falling) suggests above all that consideration needs to be given to the organization per se of the French geriatric hospital care system, and in particular to the relevance of maintaining sector-type segregation between wards for care of acute care and those involved in rehabilitatio

Incidence and main factors associated with early unplanned hospital readmission among French medical inpatients aged 75 and over admitted through emergency units

Background: among elderly patients, readmission in the month following hospital discharge is a frequent occurrence which involves a risk of functional decline, particularly among frail subjects. While previous studies have identified risk factors of early readmission, geriatric syndromes, as markers of frailty have not been assessed as potential predictors. Objective: to evaluate the risk of early unplanned readmission, and to identify predictors in inpatients aged 75 and over, admitted to medical wards through emergency departments. Design: prospective multi-centre study. Setting: nine French hospitals. Subjects: one thousand three hundred and six medical inpatients, aged 75 and older admitted through emergency departments (SAFES cohort). Methods: using logistic regressions, factors associated with early unplanned re-hospitalisation (defined as first unplanned readmission in the thirty days after discharge) were identified using data from the first week of hospital index stay obtained by comprehensive geriatric assessment. Results: data from a thousand out of 1,306 inpatients were analysed. Early unplanned readmission occurred in 14.2% of inpatients and was not related with sociodemographic characteristics, comorbidity burden or cognitive impairment. Pressure sores (OR=2.05, 95% CI = 1.0-3.9), poor overall condition (OR = 2.01, 95% CI = 1.3-3.0), recent loss of ability for self-feeding (OR = 1.9, 95% CI = 1.2-2.9), prior hospitalisation during the last 3 months (OR = 1.6, 95% CI = 1.1-2.5) were found to be risk factors, while sight disorders appeared as negatively associated (OR = 0.5, 95% CI = 0.3--0.8). Conclusions: markers of frailty (poor overall condition, pressure sores, prior hospitalisation) or severe disability (for self-feeding) were the most important predictors of early readmission among elderly medical inpatients. Early identification could facilitate preventive strategies in risk grou

The Wnt Receptor Ryk Reduces Neuronal and Cell Survival Capacity by Repressing FOXO Activity During the Early Phases of Mutant Huntingtin Pathogenicity

The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor β-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished β-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD. © 2014 Tourette et al

Update on neutrophil function in severe inflammation

Neutrophils are main players in the effector phase of the host defense against micro-organisms and have a major role in the innate immune response. Neutrophils show phenotypic heterogeneity and functional flexibility, which highlight their importance in regulation of immune function. However, neutrophils can play a dual role and besides their antimicrobial function, deregulation of neutrophils and their hyperactivity can lead to tissue damage in severe inflammation or trauma. Neutrophils also have an important role in the modulation of the immune system in response to severe injury and trauma. In this review we will provide an overview of the current understanding of neutrophil subpopulations and their function during and post-infection and discuss the possible mechanisms of immune modulation by neutrophils in severe inflammation

Design and planning of a transdisciplinary investigation into farmland pollinators: rationale, co-design, and lessons learned

To provide a complete portrayal of the multiple factors negatively impacting insects in agricultural landscapes it is necessary to assess the concurrent incidence, magnitude, and interactions among multiple stressors over substantial biogeographical scales. Trans-national ecological field investigations with wide-ranging stakeholders typically encounter numerous challenges during the design planning stages, not least that the scientific soundness of a spatially replicated study design must account for the substantial geographic and climatic variation among distant sites. ‘PoshBee’ (Pan-European assessment, monitoring, and mitigation of Stressors on the Health of Bees) is a multi-partner transdisciplinary agroecological project established to investigate the suite of stressors typically encountered by pollinating insects in European agricultural landscapes. To do this, PoshBee established a network of 128 study sites across eight European countries and collected over 50 measurements and samples relating to the nutritional, toxicological, pathogenic, and landscape components of the bees’ environment. This paper describes the development process, rationale, and end-result of each aspect of the of the PoshBee field investigation. We describe the main issues and challenges encountered during the design stages and highlight a number of actions or processes that may benefit other multi-partner research consortia planning similar large-scale studies. It was soon identified that in a multi-component study design process, the development of interaction and communication networks involving all collaborators and stakeholders requires considerable time and resources. It was also necessary at each planning stage to be mindful of the needs and objectives of all stakeholders and partners, and further challenges inevitably arose when practical limitations, such as time restrictions and labour constraints, were superimposed upon prototype study designs. To promote clarity for all stakeholders, for each sub-component of the study, there should be a clear record of the rationale and reasoning that outlines how the final design transpired, what compromises were made, and how the requirements of different stakeholders were accomplished. Ultimately, multi-national agroecological field studies such as PoshBee benefit greatly from the involvement of diverse stakeholders and partners, ranging from field ecologists, project managers, policy legislators, mathematical modelers, and farmer organisations. While the execution of the study highlighted the advantages and benefits of large-scale transdisciplinary projects, the long planning period emphasized the need to formally describe a design framework that could facilitate the design process of future multi-partner collaborations