Thinking justice outside the docket: a critical assessment of the reform of the EU's court system

The 2015 reform of the EU’s court system will go down in history as the most radical transformation of the EU judicial architecture since the establishment of the General Court in 1989. It doubles the number of General Court judges but also dissolves the Civil Service Tribunal. This article offers a critical assessment of these two major, structural changes, addressing both the process by which they were adopted and their overall merits. After providing a detailed examination of the reform’s tortuous legislative history and highlighting its unique underlying procedural feature – with the Court itself initiating the process – this article identifies and systematizes its major shortcomings. It criticizes the underlying diagnosis and the cure administered. It concludes by presenting this reform process as a missed opportunity to address, in a more holistic manner, the pressing non-docket related challenges facing the EU judicial system, in particular, to reform a governance structure which is no longer fit for purpose considering the massive transformation of the EU judicial branch since 1951

MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced platelet activation

The impact of inhibition of multidrug resistance protein 4 (MRP4) on nitric oxide (NO) resistance and on ADP-induced platelet aggregation is unknown. The aim of this investigation was to verify whether platelet NO resistance correlates with MRP4 expression and evaluate whether this can be reduced by in vitro MRP4 inhibition mediated by cilostazol. Moreover, we assessed if inhibition of MRP4-mediated transport reduces ADP-induced platelet reactivity. The inhibitory effect of sodium nitroprusside (SNP), a NO-donor that enhances cyclic guanosine monophosphate (cGMP) cytosolic concentration, was assessed in platelets obtained from aspirin treated patients and in a control population. The inhibitory effect of SNP was evaluated by ADP-induced aggregation in SNP-treated platelets. The impact of MRP4 on ADP-induced platelet aggregation was performed in high on aspirin residual platelet reactivity (HARPR) patients and compared to healthy volunteers (HV), and a control cohort (CTR). In aspirin-treated patients with high levels of MRP4, reduced SNP inhibition was found compared to those with low levels of MRP4. MRP4 inhibition by cilostazol significantly reduced ADP-induced platelet aggregation in HARPR population, and to a lesser extent in HV and CTR populations. In conclusion, cilostazol can mitigate the hyper-reactive platelet phenotype of HARPR patients by reducing residual ADP-induced platelet aggregation and increasing NO-dependent endothelial antiplatelet effects

Pregnancy, Proteinuria, Plant-Based Supplemented Diets and Focal Segmental Glomerulosclerosis: A Report on Three Cases and Critical Appraisal of the Literature.

Chronic kidney disease (CKD) is increasingly recognized in pregnant patients. Three characteristics are associated with a risk of preterm delivery or small for gestational age babies; kidney function reduction, hypertension, and proteinuria. In pregnancy, the anti-proteinuric agents (ACE–angiotensin converting enzyme-inhibitors or ARBS -angiotensin receptor blockers) have to be discontinued for their potential teratogenicity, and there is no validated approach to control proteinuria. Furthermore, proteinuria usually increases as an effect of therapeutic changes and pregnancy-induced hyperfiltration. Based on a favourable effect of low-protein diets on proteinuria and advanced CKD, our group developed a moderately protein-restricted vegan-vegetarian diet tsupplemented with ketoacids and aminoacids for pregnant patients. This report describes the results obtained in three pregnant patients with normal renal function, nephrotic or sub-nephrotic proteinuria, and biopsy proven diagnosis of focal segmental glomerulosclerosis, a renal lesion in which hyperfiltration is considered of pivotal importance (case 1: GFR (glomerular filtration rate): 103 mL/min; proteinuria 2.1 g/day; albumin 3.2 g/dL; case 2: GFR 86 mL/min, proteinuria 3.03 g/day, albumin 3.4 g/dL; case 3: GFR 142 mL/min, proteinuria 6.3 g/day, albumin 3.23 g/dL). The moderately restricted diet allowed a stabilisation of proteinuria in two cases and a decrease in one. No significant changes in serum creatinine and serum albumin were observed. The three babies were born at term (38 weeks + 3 days, female, weight 3180 g-62th centile; 38 weeks + 2 days, female, weight 3300 g-75th centile; male, 38 weeks + 1 day; 2770 g-8th centile), thus reassuring us of the safety of the diet. In summary, based on these three cases studies and a review of the literature, we suggest that a moderately protein-restricted, supplemented, plant-based diet might contribute to controlling proteinuria in pregnant CKD women with focal segmental glomerulosclerosis. However further studies are warranted to confirm the potential value of such a treatment strategy

Probing Single-Cell Fermentation Fluxes and Exchange Networks via pH-Sensing Hybrid Nanofibers

The homeostatic control of their environment is an essential task of living cells. It has been hypothesized that, when microenvironmental pH inhomogeneities are induced by high cellular metabolic activity, diffusing protons act as signaling molecules, driving the establishment of exchange networks sustained by the cell-to-cell shuttling of overflow products such as lactate. Despite their fundamental role, the extent and dynamics of such networks is largely unknown due to the lack of methods in single-cell flux analysis. In this study, we provide direct experimental characterization of such exchange networks. We devise a method to quantify single-cell fermentation fluxes over time by integrating high-resolution pH microenvironment sensing via ratiometric nanofibers with constraint-based inverse modeling. We apply our method to cell cultures with mixed populations of cancer cells and fibroblasts. We find that the proton trafficking underlying bulk acidification is strongly heterogeneous, with maximal single-cell fluxes exceeding typical values by up to 3 orders of magnitude. In addition, a crossover in time from a networked phase sustained by densely connected "hubs" (corresponding to cells with high activity) to a sparse phase dominated by isolated dipolar motifs (i.e., by pairwise cell-to-cell exchanges) is uncovered, which parallels the time course of bulk acidification. Our method addresses issues ranging from the homeostatic function of proton exchange to the metabolic coupling of cells with different energetic demands, allowing for real-time noninvasive singlecell metabolic flux analysis

Evaluation of the diagnostic accuracy of three memory tests for early Alzheimer's disease (pe-2013-02356465) : a preliminary report

Aims: The main aim of this multicentric longitudinal project is to investigate the specificity and sensitivity of three memory tests (FCSRT, STMBT, DMS48) proposed as cognitive marker for Alzheimer's disease (AD). Here, we report preliminary baseline data on healthy controls, people with MCI and patients with AD. Subjects and methods: Data collected on 13 AD, 16 MCI, 16 healthy older (HO) and 16 healthy younger (HY) adults were analysed. All participants underwent the three experimental tests along with a standard neuropsychological evaluation in one single session. Results: For the FCSRT, a three-way ANOVA with GROUP as the between-subjects factor and TASK (free, cued) and TIME (immediate, delayed) as within-subjects measures revealed a significant effect of GROUP (HY = HO > MCI > AD; p free, ; p delayed; p MCI > AD; p paired = abstract; p HO > MCI > AD; p 3; p binding; p< .001) and a significant interaction between STIMULUS and GROUP (p= .003). Discussion: The present report study shows reports for the first time a comparison across Controls, MCI and AD on three memory tests proposed as cognitive markers for AD. For the FCSRT both the timing of recall and the presence of a cue are relevant factors to influence patient performances. For the DMS48 the most sensitive indexes to differentiate between controls and patients are the unpaired and abstract items, while for the STMBT the binding condition is more affected in patients are regardless of the number of items presented are. These preliminary data are encouraging in confirming that these tests may offer an aid to diagnosis of early AD, but a larger sample and longitudinal data are needed to address the main research question of this planned study. *** References: Barbeau, E, Didic, M, Tramoni, E, Felician, O, Joubert, S, Sontheimer, A, Ceccaldi, M, Poncet, M. (2004). Evaluation of visual recognition memory in MCI patients. Neurology 62, 1317-1322. Frasson P, Ghiretti R, Catricala E, Pomati S, Marcone A, Parisi L, Rossini PM, Cappa SF, Mariani C, Vanacore N, Clerici F (2011) Free and cued selective reminding test: an Italian normative study. Neurological Sciences 32:1057-1062 Parra MA, Abrahams S, Fabi K, Logie R, Luzzi S, Della Sala S (2009) Short-term memory binding deficits in Alzheimer's disease. Brain 132:1057-106

Probing Single-Cell Fermentation Fluxes and Exchange Networks via pH-Sensing Hybrid Nanofibers [Dataset]

37 pages. -- Further details on experimental methods: Synthesis of particle-based pH-sensors. -- Fabrication of pH-sensing hybrid nanofibers. -- Characterization of pH-sensing hybrid nanofibers. -- Calibration of pH-sensing hybrid nanofibers. -- Cell proliferation assay. -- Cell co-cultures on pH-sensing hybrid nanofibers. -- Extracellular lactate quantification. -- Statistical significance. -- Sensing of pH in the cell cultures over time. -- Further details on image analysis: [A] Particle (cell or sensor) detection. -- [B] Intensity Evaluation. -- [C] Tracking cells and probes across frames. -- Further details on computational methods: Gaussian approximation. -- Enforcing positivity constraints of the reconstructed concentration profile. -- Priors and Lagrange multipliers: Tikhonov regularizer for the scale !1. -- Time continuity across frames !2. -- Matching the bulk trend !3. -- The Monte Carlo Markov chain. -- Errors and confidence interval. -- Ruling out flow contributions from advection. -- Flux distributions conditioned on the cell type. -- pH maps. -- Supporting files description. - Data. -- Codes. -- Supplementary Figures.The homeostatic control of their environment is an essential task of living cells. It has been hypothesized that, when microenvironmental pH inhomogeneities are induced by high cellular metabolic activity, diffusing protons act as signaling molecules, driving the establishment of exchange networks sustained by the cell-to-cell shuttling of overflow products such as lactate. Despite their fundamental role, the extent and dynamics of such networks is largely unknown due to the lack of methods in single-cell flux analysis. In this study, we provide direct experimental characterization of such exchange networks. We devise a method to quantify single-cell fermentation fluxes over time by integrating high-resolution pH microenvironment sensing via ratiometric nanofibers with constraint-based inverse modeling. We apply our method to cell cultures with mixed populations of cancer cells and fibroblasts. We find that the proton trafficking underlying bulk acidification is strongly heterogeneous, with maximal single-cell fluxes exceeding typical values by up to 3 orders of magnitude. In addition, a crossover in time from a networked phase sustained by densely connected “hubs” (corresponding to cells with high activity) to a sparse phase dominated by isolated dipolar motifs (i.e., by pairwise cell-to-cell exchanges) is uncovered, which parallels the time course of bulk acidification. Our method addresses issues ranging from the homeostatic function of proton exchange to the metabolic coupling of cells with different energetic demands, allowing for real-time noninvasive single-cell metabolic flux analysis.Peer reviewe

Vegan-vegetarian low-protein supplemented diets in pregnant CKD patients: fifteen years of experience

Background: Pregnancy in women with advanced CKD becoming increasingly common. However, experience with low-protein diets in CKD patients in pregnancy is still limited. Aim of this study is to review the results obtained over the last 15 years with moderately restricted low-protein diets in pregnant CKD women (combining: CKD stages 3-5, proteinuria: nephrotic at any time, or &gt; =1 g/24 at start or referral; nephrotic in previous pregnancy). CKD patients on unrestricted diets were employed for comparison. Methods: Study period: January, 2000 to September, 2015: 36 on-diet pregnancies (31 singleton deliveries, 3 twin deliveries, 1 pregnancy termination, 1 miscarriage); 47 controls (42 singleton deliveries, 5 miscarriages). The diet is basically vegan; since occasional milk and yoghurt are allowed, we defined it vegan-vegetarian; protein intake (0.6-0.8 g/Kg/day), keto-acid supplementation, protein-unrestricted meals (1-3/week) are prescribed according to CKD stage and nutritional status. Statistical analysis was performed as implemented on SPSS. Results: Patients and controls were similar (p: ns) at baseline with regard to age (33 vs 33.5), referral week (7 vs 9), kidney function (CKD 3-5: 48.4 % vs 64.3 %); prevalence of hypertension (51.6 % vs 40.5 %) and proteinuria &gt;3 g/24 h (16.1 % vs 12.2 %). There were more diabetic nephropathies in on-diet patients (on diet: 31.0 % vs controls 5.3 %; p 0.007 (Fisher)) while lupus nephropathies were non-significantly higher in controls (on diet: 10.3 % vs controls 23.7 %; p 0.28 (Fisher)). The incidence of preterm delivery was similar (&lt;37 weeks: on-diet singletons 77.4 %; controls: 71.4 %). The incidence of other adverse pregnancy related outcomes was non-significantly lower in on-diet patients (early preterm delivery: on diet: 32.3 % vs controls 35.7 %; birth-weight = &lt;1.500 g: on diet: 9.7 % vs controls 23.8 %). None of the singletons in the on-diet series died, while two perinatal deaths occurred among the controls (p = 0.505). The incidence of small for gestational age (SGA &lt;10th centile) and/or extremely preterm babies (&lt;28th week) was significantly lower in singletons from on-diet mothers than in controls (on diet: 12.9 % vs controls: 33.3 %; p: 0.04 (Fisher)). Conclusion: Moderate protein restriction in the context of a vegan-vegetarian supplemented diet is confirmed as a safe option in the management of pregnant CKD patients

Emergency hernia repair in the elderly. multivariate analysis of morbidity and mortality from an Italian registry

Purpose The incidence of inguinal hernia is higher in elderly because of aging-related diseases like prostatism, bronchitis, collagen laxity. A conservative management is common in elderly to reduce surgery-related risks, however watchful waiting can expose to obstruction and strangulation. The aim of the present study was to assess the impact of emergency surgery in a large series of elderly with complicated groin hernia and to identify the independent risk factors for postoperative morbidity and mortality. The predictive performance of prognostic risk scores has been also assessed. Methods This is a prospective observational study carried out between January 2017 and June 2018 in elderly patients who underwent emergency surgery for complicated hernia in 38 Italian hospitals. Pre-operative, surgical and postoperative data were recorded for each patient. ASA score, Charlson's comorbidity index, P-POSSUM and CR-POSSUM were assessed. Results 259 patients were recruited, mean age was 80 years. A direct repair without mesh was performed in 62 (23.9%) patients. Explorative laparotomy was performed in 56 (21.6%) patients and bowel resection was necessary in 44 (17%). Mortality occurred in seven (2.8%) patients. Fifty-five (21.2%) patients developed complications, 12 of whom had a major one. At univariate and multivariate analyses, Charlson's comorbidity index &gt;= 6, altered mental status, and need for laparotomy were associated with major complications and mortality Conclusion Emergency surgery for complicated hernia is burdened by high morbidity and mortality in elderly patients. Preoperative comorbidity played a pivotal role in predicting complications and mortality and therefore Charlson's comorbidity index could be adopted to select patients for elective operation