Warm renal ischemia performed during partial nephrectomy has been found to be associated with kidney disease. Since endogenous ouabain (EO) is a neuro-endocrine hormone involved in renal damage, we ...evaluated the role of EO in renal ischemia-reperfusion injury (IRI). We measured plasma and renal EO variations and markers of glomerular and tubular damage (nephrin, KIM-1, Kidney-Injury-Molecule-1, α1 Na-K ATPase) and the protective effect of the ouabain inhibitor, rostafuroxin. We studied five groups of rats: (1) normal; (2) infused for eight weeks with ouabain (30 µg/kg/day, OHR) or (3) saline; (4) ouabain; or (5) saline-infused rats orally treated with 100 µg/kg/day rostafuroxin for four weeks. In group 1, 2-3 h after IRI, EO increased in ischemic kidneys while decreased in plasma. Nephrin progressively decreased and KIM-1 mRNA increased starting from 24 h. Ouabain infusion (group 2) increased blood pressure (from 111.7 to 153.4 mmHg) and ouabain levels in plasma and kidneys. In OHR ischemic kidneys at 120 h from IRI, nephrin, and KIM-1 changes were greater than those detected in the controls infused with saline (group 3). All these changes were blunted by rostafuroxin treatment (groups 4 and 5). These findings support the role of EO in IRI and suggest that rostafuroxin pre-treatment of patients before partial nephrectomy with warm ischemia may reduce IRI, particularly in those with high EO.
The transient receptor potential melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity is available. This study ...characterizes a new TRPM8-selective antagonist (DFL23448 5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol) and evaluates it in cold-induced behavioral tests and tests on bladder function and experimental bladder overactivity in vivo in rats. DFL23448 displayed IC50 values of 10 and 21 nM in hTRPM8 human embryonic kidney 293 cells activated by Cooling Agent 10 or cold, but it had limited activity (IC50 > 10 μM) at transient receptor potential vanilloids TRPV1, TRPA1, or TRPV4 or at various G protein-coupled receptors. In rats, DFL23448 administered intravenously or orally had a half-life of 37 minutes or 4.9 hours, respectively. DLF23448 (10 mg/kg i.v.) reduced icilin-induced "wet dog-like" shakes in rats. Intravesical DFL23448 (10 mg/l), but not vehicle, increased micturition intervals, micturition volume, and bladder capacity. During bladder overactivity by intravesical prostaglandin E2 (PGE2), vehicle controls exhibited reductions in micturition intervals, micturition volumes, and bladder capacity by 37%-39%, whereas the same parameters only decreased by 12%-15% (P < 0.05-0.01 versus vehicle) in DFL23448-treated rats. In vehicle-treated rats, but not in DFL23448-treated rats, intravesical PGE2 increased bladder pressures. Intravenous DFL23448 at 10 mg/kg, but not 1 mg/kg DFL23448 or vehicle, increased micturition intervals, micturition volumes, and bladder capacity. During bladder overactivity by intravesical PGE2, micturition intervals, micturition volumes, and bladder capacity decreased in vehicle- and 1 mg/kg DFL23448-treated rats, but not in 10 mg/kg DFL23448-treated rats. Bladder pressures increased less in rats treated with DFL23448 10 mg/kg than in vehicle- or 1 mg/kg DFL23448-treated rats. DFL23448 (10 mg/kg i.v.), but not vehicle, prevented cold stress-induced bladder overactivity. Our results support a role for bladder TRPM8-mediated signals in experimental bladder overactivity.
The inhibitory effects demonstrated by activation of cannabinoid receptors (CB) on cancer proliferation and migration may also play critical roles in controlling bladder cancer (BC). CB expression on ...human normal and BC specimens was tested by immunohistochemistry. Human BC cells RT4 and RT112 were challenged with CB agonists and assessed for proliferation, apoptosis, and motility. Cellular sphingolipids (SL) constitution and metabolism were evaluated after metabolic labelling. CB1-2 were detected in BC specimens, but only CB2 was more expressed in the tumour. Both cell lines expressed similar CB2. Exposure to CB2 agonists inhibited BC growth, down-modulated Akt, induced caspase 3-activation and modified SL metabolism. Baseline SL analysis in cell lines showed differences linked to unique migratory behaviours and cytoskeletal re-arrangements. CB2 activation changed the SL composition of more aggressive RT112 cells by reducing (p < 0.01) Gb3 ganglioside (-50 ± 3%) and sphingosine 1-phosphate (S1P, -40 ± 4%), which ended up to reduction in cell motility (-46 ± 5%) with inhibition of p-SRC. CB2-selective antagonists, gene silencing and an inhibitor of SL biosynthesis partially prevented CB2 agonist-induced effects on cell viability and motility. CB2 activation led to ceramide-mediated BC cell apoptosis independently of SL constitutive composition, which instead was modulated by CB2 agonists to reduce cell motility.
Healthcare Associated Infections (HAIs) and Antimicrobial Resistance (AMR) are serious health challenges. Point prevalence surveys (PPS) are valuable tools for monitoring HAIs and AMR.
To describe ...results of the ECDC-PPS 2022 dealing with the prevalence of HAIs, antimicrobial consumption, and associated factors, in acute care hospitals.
The present point-prevalence have been carried out survey in November 2022 in fourteen hospitals according to the protocol proposed by the European Centre for Disease Prevention and Control (ECDC). Multilevel logistic regression was performed using geographical area/hospital type as cluster variable to evaluate the factors independently associated with HAIs and antibiotics.
The point prevalence of HAIs was 7.43%. Patients hospitalized for longer periods were more likely to have an HAI as well as those aged 15-44, with a rapidly fatal disease, intubated and with 1 or 2 devices. Antibiotics prevalence was 47.30%. Males, unknown McCabe scores, minimally invasive/non-NHSN surgery, patients with HAIs, hospitals with a higher alcohol hand rub consumption, hospitals with a higher amount of IPC personnel, geriatric wards and hospital with 300-600 beds were more likely to be under antimicrobial therapy.
This point prevalence survey provided valuable information on the prevalence of HAIs and antimicrobial consumption and variables associated. The high prevalence of HAIs highlights the need for improved infection control measures.
Abstract Background The schedule for intravesical chemotherapy administration has not been definitively established in patients with low-grade recurrent non–muscle-invasive bladder cancer (NMIBC). ...Objective To assess both the feasibility and the efficacy of a short-term intensive schedule of neoadjuvant intravesical chemotherapy in patients with recurrent NMIBC. Design, setting, and participants A randomised phase 2 clinical study included 54 patients with recurrent NMIBC who were submitted to neoadjuvant chemotherapy intravesical instillations according to two different timing schedules. The study was performed at a tertiary care referral centre. Intervention Intravesical mitomycin C (MMC) 40 mg/40 ml was administered according to a schedule of either one instillation per week for 6 wk (group 1) or three instillations per week for 2 wk (group 2) prior to transurethral resection (TUR). Outcome measurements and statistical analysis Local and systemic toxicity were investigated using the US National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.0 questionnaire at each instillation and the SF-36 questionnaire at randomisation and before TUR. A video-recorded cystoscopy and TUR were performed within 14 d after treatment completion. Results and limitations Groups 1 and 2 each were assigned 27 cases. Two patients (7.4%) in group 2 could not complete the scheduled treatment because of severe lower urinary tract symptoms. No statistically significant difference in SF-36 domain score was documented pre- and post-treatment between groups. Likewise, no statistically significant difference in treatment-related toxicity according to the CTCAE v.4 questionnaire was registered. Twelve patients (44.4%) in group 1 and 19 patients (70.4%) in group 2 ( p = 0.04) had complete tumour response. The small number of patients included represents the main limitation of the study. Conclusions The intensive short-term schedule of neoadjuvant chemotherapy is safe and without additional toxicity compared with the weekly regimen. The increased ablative effect may be explained by the improved adherence of the scheduled timing to the duplication rate of tumour cells.
Following a request from the European Commission, EFSA developed updated scientific guidance to assist applicants in the preparation of applications on smoke flavouring primary products. This ...guidance describes the scientific data to be included in the applications for the authorisation of new smoke flavouring primary products, as well as for the renewal or for the modification of existing authorisations, submitted respectively under Articles 7, 12 and 11 of Regulation (EC) No 2065/2003. Information to be provided in all applications relates to: the characterisation of the primary product, including the description of the source materials, manufacturing process, chemical composition, specifications and stability; the proposed uses and use levels and the assessment of the dietary exposure; the safety data, including information on the genotoxic potential of the identified components and of the unidentified fraction of the primary product, toxicological data other than genotoxicity and information on the safety for the environment. For the toxicological studies a tiered approach is applied, for which the testing requirements, key issues and triggers are described. A description of the standard uncertainties relevant for the evaluation of primary products and how these are considered in the standardised risk assessment procedure is also included. The applicant should generate the data requested in each section to support the safety assessment of the smoke flavouring primary product. On the basis of the submitted data, EFSA will assess the safety of the primary product and conclude whether or not it presents risks to human health and to the environment under the proposed conditions of use.
The Panel on Food Additives and Flavourings (FAF) was requested to consider the JECFA evaluations of 28 flavouring substances in the Flavouring Group Evaluation 76 (FGE.76Rev2). Twenty‐one of these ...substances have been considered in FGE.76Rev1. Seven substances could not be evaluated, because of concerns with respect to genotoxicity. New genotoxicity data have been provided for 4‐methyl‐5‐vinylthiazole FL‐no: 15.018 and 4,5‐dimethyl‐2‐isobutyl‐3‐thiazoline FL‐no: 15.032, which are representative substances of FL‐no: 15.005 and FL‐no: 15.029, 15.030, 15.130 and 15.131, respectively. The Panel concluded that the concern for genotoxicity is ruled out for FL‐no: 15.018 and 15.005. The concerns for gene mutations and clastogenicity are ruled out for FL‐no: 15.032, 15.029, 15.030, 15.130 and 15.131. In vitro, FL‐no: 15.032 induced micronuclei through an aneugenic mode of action. The available in vivo micronucleus study was not adequate to rule out the concern for potential aneugenicity in vivo. The Panel compared the lowest concentration resulting in aneugenicity in vitro with the use levels reported for FL‐no: 15.032. Based on this comparison, the Panel concluded that the use of FL‐no: 15.032 at the maximum reported use levels does not raise a concern for aneugenicity. Based on structural similarity, for the remaining four substances FL‐no: 15.029, 15.030, 15.130 and 15.131, an aneugenic potential may also be anticipated. Individual genotoxicity data are needed to establish whether they have aneugenic potential. The Panel agrees with JECFA conclusions for 24 flavouring substances ‘No safety concern at estimated levels of intake as flavouring substances’ when based on the MSDI approach. For six substances, more reliable information on uses and use levels are needed to refine the mTAMDI estimates. For 15 substances, use levels are needed to calculate the mTAMDIs. For FL‐no: 15.109 and 15.113, information on the actual stereochemical composition is inadequate and the conclusion reached for the named substances cannot be applied to the materials of commerce.
The Panel on Food Additives and Flavourings (FAF) was requested to consider the JECFA evaluations of 25 flavouring substances assigned to the Flavouring Group Evaluation 67 (FGE.67Rev3), using the ...Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Eleven substances have already been considered in FGE.67 and its revisions (FGE.67Rev1 and FGE.67Rev2). During the current assessment, two substances were no longer supported by industry, therefore 12 candidate substances are evaluated in FGE.67Rev3. New genotoxicity and toxicity data are available for 2‐pentylfuran FL‐no: 13.059 and 2‐acetylfuran FL‐no: 13.054, which are representative substances of subgroup IV FL‐no: 13.069, 13.106, 13.148 and VI‐B FL‐no: 13.045, 13.070, 13.083, 13.101, 13.105, 13.138, 13.163, respectively. Based on these data, the Panel concluded that the concern for genotoxicity is ruled out for both FL‐no: 13.054 and FL‐no: 13.059 and consequently for the substances that they represent. Since the candidate substances cannot be anticipated to be metabolised to innocuous products only, they were evaluated along the B‐side of the Procedure. The Panel derived a NOAEL of 22.6 mg/kg bw per day and a BMDL of 8.51 mg/kg bw per day, for 2‐acetylfuran and 2‐pentylfuran, respectively. For all 12 substances sufficient margins of safety were calculated when based on the MSDI approach. Adequate specifications for the materials of commerce are available for all 23 flavouring substances. The Panel agrees with JECFA conclusions, for all 23 substances, ‘No safety concern at estimated levels of intake as flavouring substances’ based on the MSDI approach. For 18 substances FL‐no: 13.021, 13.022, 13.023, 13.024, 13.031, 13.045, 13.047, 13.054, 13.059, 13.074, 13.083, 13.101, 13.105, 13.106, 13.138, 13.148, 13.163 and 13.190, the mTAMDI intake estimates are above the threshold of toxicological concern (TTC) for their structural classes and more reliable data on uses and use levels are required to finalise their evaluation.
Following a request from the European Commission, EFSA developed a new scientific guidance to assist applicants in the preparation of applications for the authorisation of flavourings to be used in ...or on foods. This guidance applies to applications for a new authorisation as well as for a modification of an existing authorisation of a food flavouring, submitted under Regulation (EC) No 1331/2008. It defines the scientific data required for the evaluation of those food flavourings for which an evaluation and approval is required according to Article 9 of Regulation (EC) No 1334/2008. This applies to flavouring substances, flavouring preparations, thermal process flavourings, flavour precursors, other flavourings and source materials, as defined in Article 3 of Regulation (EC) No 1334/2008. Information to be provided in all applications relates to: (a) the characterisation of the food flavouring, including the description of its identity, manufacturing process, chemical composition, specifications, stability and reaction and fate in foods; (b) the proposed uses and use levels and the assessment of the dietary exposure and (c) the safety data, including information on the genotoxic potential of the food flavouring, toxicological data other than genotoxicity and information on the safety for the environment. For the toxicological studies, a tiered approach is applied, for which the testing requirements, key issues and triggers are described. Applicants should generate the data requested in each section to support the safety assessment of the food flavouring. Based on the submitted data, EFSA will assess the safety of the food flavouring and conclude whether or not it presents risks to human health and to the environment, if applicable, under the proposed conditions of use.
This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2022.EN-7669/full
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