Dose of colistin. a work in progress?

We thank Rashid and colleagues [1] and Honoré and colleagues [2] for their comments regarding our article on risk factors for acute kidney injury in pa- tients receiving colistin or other nephrotoxic antimi- crobials [3]. It is correct that we did not specifically report urine output in the text, but it was obviously included in the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria reported in Table two [3]

Pd@TiO2/carbon nanohorn electrocatalysts: reversible CO2 hydrogenation to formic acid

Direct conversion of carbon dioxide to formic acid at thermodynamic equilibrium is an advantage of enzymatic catalysis, hardly replicated by synthetic analogs, but of high priority for carbon-neutral energy schemes. The bio-mimetic potential of totally inorganic Pd@TiO2 nanoparticles is envisioned herein in combination with Single Walled Carbon NanoHorns (SWCNHs). The high surface nano-carbon entanglement templates a wide distribution of \u201chard-soft\u201d bimetallic sites where the small Pd nanoparticles (1.5 nm) are shielded within the TiO2 phase (Pd@TiO2), while being electrically wired to the electrode by the nanocarbon support. This hybrid electrocatalyst activates CO2 reduction to formic acid at near zero overpotential in the aqueous phase (onset potential at E < 120.05 V vs. RHE, pH = 7.4), while being able to evolve hydrogen via sequential formic acid dehydrogenation. The net result hints at a unique CO2 \u201ccircular catalysis\u201d where formic acid versus H2 selectivity is addressable by flow-reactor technology

Mechanisms involved in the promoting activity of fibroblasts in HTLV-1-mediated lymphomagenesis: Insights into the plasticity of lymphomatous cells

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10+GPR77+ HFF subpopulation, but also the percentage of ALDH1bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings

Towards an EU Charter of the Fundamental Rights of Nature

This Study aims to set a framework for the legal recognition of the Rights of Nature in the EU legal order, as a prerequisite for a different and improved relationship between human beings and Nature. This aim should be possibly accomplished through the development of a EU Charter on Fundamental Rights of Nature. Initially, the Study shows the role of Rights of Nature with respect to environmental protection goals and addresses the reasons why current EU Environmental Law is failing to deliver the required level of nature protection (Section 2). Subsequently, the Study assesses how the "Rights of Nature" may help to overcome the failures of environmental law. To this end, four paradigmatic cases are proposed and analysed (Section 3). Based on the findings of this analysis, the strategic milestones required to achieve genuine ecosystem protection are identified and presented (Section 4). Finally, the possibility of introducing a Charter of the Rights of Nature in the EU legal system, with its basic principles, recommendable features and proposed pathway is discussed (Sections 5, 6 and 7)

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University

Post-transplant recurrence of steroid resistant nephrotic syndrome in children: the Italian experience

Background: Steroid resistant nephrotic syndrome (SRNS) is a frequent cause of end stage renal disease in children and post-transplant disease recurrence is a major cause of graft loss. Methods: We identified all children with SRNS who underwent renal transplantation in Italy, between 2005 and 2017. Data were retrospectively collected for the presence of a causative gene mutation, sex, histology, duration of pre-transplant dialysis, age at onset and transplant, HLA matching, recurrence, therapy for recurrence, and graft survival. Results: 101 patients underwent a first and 22 a second renal transplant. After a median follow-up of 58.5&nbsp;months, the disease recurred on the first renal transplant in 53.3% of patients with a non-genetic and none with a genetic SRNS. Age at transplant &gt; 9&nbsp;years and the presence of at least one HLA-AB match were independent risk factors for recurrence. Duration of dialysis was longer in children with relapse, but did not reach statistical significance. Overall, 24% of patients lost the first graft, with recurrence representing the commonest cause. Among 22 patients who underwent a second transplant, 5 suffered of SRNS recurrence. SRNS relapsed in 5/9 (55%) patients with disease recurrence in their first transplant and 2 of them lost the second graft. Conclusions: Absence of a causative mutation represents the major risk factor for post-transplant recurrence in children with SRNS, while transplant can be curative in genetic SRNS. A prolonged time spent on dialysis before transplantation has no protective effect on the risk of relapse and should not be encouraged. Retransplantation represents a second chance after graft loss for recurrence

Oral steroids for reducing kidney scarring in young children with febrile urinary tract infections: the contribution of Bayesian analysis to a randomized trial not reaching its intended sample size

Background: This study aimed to evaluate the effect of oral dexamethasone in reducing kidney scars in infants with a first febrile urinary tract infection (UTI). Methods: Children aged between 2 and 24 months with their first presumed UTI, at high risk for kidney scarring based on procalcitonin levels ( 651 ng/mL), were randomly assigned to receive dexamethasone in addition to routine care or routine care only. Kidney scars were identified by kidney scan at 6 months after initial UTI. Projections of enrollment and follow-up completion showed that the intended sample size could not be reached before funding and time to complete the study ran out. An amendment to the protocol was approved to conduct a Bayesian analysis. Results: We randomized 48 children, of whom 42 had a UTI and 18 had outcome kidney scans (instead of 128 planned). Kidney scars were found in 0/7 and 2/11 patients in the treatment and control groups respectively. The probability that dexamethasone could prevent kidney scarring was 99% in the setting of an informative prior probability distribution (which fully incorporated in the final inference the information on treatment effect provided by previous studies) and 98% in the low-informative scenario (which discounted the prior literature information by 50%). The probabilities that dexamethasone could reduce kidney scar formation by up to 20% were 61% and 53% in the informative and low-informative scenario, respectively. Conclusions: Dexamethasone is highly likely to reduce kidney scarring, with a more than 50% probability to reduce kidney scars by up to 20%. Trial registration number: EudraCT number: 2013-000388-10; registered in 2013 (prospectively registered) Graphical Abstract: [Figure not available: see fulltext.

How Covid-19 changed the epidemiology of febrile urinary tract infections in children in the emergency department during the first outbreak

Background: The first Covid-19 pandemic affected the epidemiology of several diseases. A general reduction in the emergency department (ED) accesses was observed during this period, both in adult and pediatric contexts. Methods: This retrospective study was conducted on the behalf of the Italian Society of Pediatric Nephrology (SINePe) in 17 Italian pediatric EDs in March and April 2020, comparing them with data from the same periods in 2018 and 2019. The total number of pediatric (age 0–18 years) ED visits, the number of febrile urinary tract infection (UTI) diagnoses, and clinical and laboratory parameters were retrospectively collected. Results: The total number of febrile UTI diagnoses was 339 (73 in 2020, 140 in 2019, and 126 in 2018). During the first Covid-19 pandemic, the total number of ED visits decreased by 75.1%, the total number of febrile UTI diagnoses by 45.1%, with an increase in the UTI diagnosis rate (+ 121.7%). The data collected revealed an increased rate of patients with two or more days of fever before admission (p = 0.02), a significant increase in hospitalization rate (+ 17.5%, p = 0.008) and also in values of C reactive protein (CRP) (p = 0.006). In 2020, intravenous antibiotics use was significantly higher than in 2018 and 2019 (+ 15%, p = 0.025). Urine cultures showed higher Pseudomonas aeruginosa and Enterococcus faecalis percentages and lower rates of Escherichia coli (p = 0.02). Conclusions: The first wave of the Covid-19 pandemic had an essential impact on managing febrile UTIs in the ED, causing an absolute reduction of cases referring to the ED but with higher clinical severity. Children with febrile UTI were more severely ill than the previous two years, probably due to delayed access caused by the fear of potential hospital-acquired Sars-Cov-2 infection. The possible increase in consequent kidney scarring in this population should be considered

Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial.

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses ( 650.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for 651 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for 6460 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS