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Wet age-related macular degeneration (wAMD) is a chronic inflammation-associated neurodegenerative disease affecting the posterior part of the eye in the aging population. Aging results in the reduced functionality of cells and tissues, including the cells of the retina. Initiators of a chronic inflammatory and pathologic state in wAMD may be a result of the accumulation of inevitable metabolic injuries associated with the maintenance of tissue homeostasis from a young age to over 50. Apart from this, risk factors like smoking, genetic predisposition, and failure to repair the injuries that occur, alongside attempts to rescue the hypoxic outer retina may also contribute to the pathogenesis. Aging of the immune system (immunosenescence) and a compromised outer blood retinal barrier (BRB) result in the exposure of the privileged milieu of the retina to the systemic immune system, further increasing the severity of the disease. When immune-privileged sites like the retina are under pathological stress, certain age- and disease-related conditions may necessitate assistance from cells distant from the resident ones to help restore the functionality of the tissue. As a necessary part of tissue repair, inflammation is a major response to disease and recruits immune cells to the site of damage. We suspect that the specific reparative inflammatory responses are controlled by an autoantigen-T cell-mediated mechanism, a process that may be hindered in wAMD.

Impaired adipogenesis has been shown to predispose to disturbed adipocyte function and development of metabolic abnormalities. Previous studies indicate that polyamines are essential in the adipogenesis in 3T3‐L1 fibroblasts. However, the specific roles of individual polyamines during adipogenesis have remained ambiguous as the natural polyamines are readily interconvertible inside the cells. Here, we have defined the roles of spermidine and spermine in adipogenesis of 3T3‐L1 cells by using (S’)‐ and (R’)‐ isomers of α‐methylspermidine and (S,S’)‐, (R,S)‐ and (R,R’)‐diastereomers of α,ω‐bismethylspermine. Polyamine depletion caused by α‐difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, prevented adipocyte differentiation by suppressing the expression of its key regulators, peroxisome proliferator‐activated receptor γ and CCAAT/enhancer binding protein α. Adipogenesis was restored by supplementation of methylspermidine isomers but not of bismethylspermine diastereomers. Although both spermidine analogues supported adipocyte differentiation only (S)‐methylspermidine was able to fully support cell growth after extended treatment with α‐DFMO. The distinction between the spermidine analogues in maintaining growth was found to be in their different capability to maintain functional hypusine synthesis. However, the differential ability of spermidine analogues to support hypusine synthesis did not correlate with their ability to support differentiation. Our results show that spermidine, but not spermine, is essential for adipogenesis and that the requirement of spermidine for adipogenesis is not strictly associated with hypusine modification. The involvement of polyamines in the regulation of adipogenesis may offer a potential application for the treatment of dysfunctional adipocytes in patients with obesity and metabolic syndrome.

The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using genetic reporter, fate mapping, and in situ hybridization, we found Angpt4 expression in a specific sub-population of astrocytes at the site where venous morphogenesis occurs and that lower oxygen tension, which distinguishes peripheral and venous locations, enhances Angpt4 expression. Correlating with its spatiotemporal expression, deletion of Angpt4 resulted in defective venous development causing impaired venous drainage and defects in neuronal cells. In vitro characterization of angiopoietin-4 proteins revealed both ligand-specific and redundant functions among the angiopoietins. Our study identifies Angpt4 as the first growth factor for venous-specific development and its importance in venous remodeling, retinal fluid clearance and neuronal function.

BackgroundThe extracellular volume (ECV) and intracellular volume (ICV) estimated by bioimpedance analysis (BIA) deviates markedly from the textbook volumes of 20% and 40% of the body weight (BW). We estimated the transcellular exchange of water by calculating solute equilibriums after fluid challenges to examine whether the BIA or the textbook volumes are likely to be most correct.MethodsData was retrieved from 8 healthy male volunteers who received 25 mL/kg of Ringer’s solution or 3–5 mL/kg of hypertonic (7.5%) saline over 30 min after the ECV and ICV had been estimated by BIA. The exchange of water between the ECV and the ICV was calculated according to a sodium equation and an osmolality equation. Simulations were performed, where deviating body fluid volumes were applied.ResultsThe mean ECV measured with BIA was 24.9% of BW (p < 0.05 versus the “textbook” volume). Mean ICV measured with BIA was 22.3% of BW (p < 0.05). The sodium and osmolality equations correlated closely with respect to the translocation of water across the cell membrane (r2 = 0.86). By applying the “textbook” ECV, the sodium equation indicated that Ringer’s solution exchanged negligible amounts of water, while hypertonic saline withdrew 1.4 L from the ICV to the ECV. By contrast, applying the BIA-derived ECV to the sodium equation implied that 3 L of water would be translocated from the ECV to the ICV once hypertonic saline was administered.ConclusionThe “textbook” ECV and ICV volumes but not the BIA-derived volumes were consistent with the fluid shifts obtained by two solute equations.

Background: The use of durable left ventricular assist devices (LVADs) for advanced heart failure is increasing and a growing number of patients will require anesthesia for non-cardiac procedures (NCPs). The goal of this study was to describe our experience with NCPs for LVAD patients. Methods: All anesthetic procedures performed in LVAD patients at a single center were reviewed from 2014 to 2023. Perioperative management data and complications were assessed. Results: In total, 16 patients had an LVAD implanted and 9 (56.3%) patients underwent anesthesia for a total of 22 NCPs. Most of the procedures took place outside of the operating room, mainly in the endoscopy unit, as gastrointestinal endoscopy was the most common procedure (13, 59.2%). Sedation was provided in 17 procedures (77.3%). Standard monitoring was used in all cases, and invasive monitoring was applied just in cases of major surgeries. There were no intraoperative complications reported. Postoperative complications were recorded after eight (36.4%) of the procedures, consisting mainly of lower gastrointestinal bleeding after lower endoscopy, which increased the length of hospital stay. All procedures were performed by non-cardiac anesthesiologists. Conclusions: Our data suggest that, in most cases, adherence to standard anesthesia practices can be suitable for NCPs in LVAD patients.

PurposeTo document and analyse the decision to withhold or withdraw life-sustaining treatment (LST) in a population of very old patients admitted to the ICU.MethodsThis prospective study included intensive care patients aged ≥ 80 years in 309 ICUs from 21 European countries with 30-day mortality follow-up.ResultsLST limitation was identified in 1356/5021 (27.2%) of patients: 15% had a withholding decision and 12.2% a withdrawal decision (including those with a previous withholding decision). Patients with LST limitation were older, more frail, more severely ill and less frequently electively admitted. Patients with withdrawal of LST were more frequently male and had a longer ICU length of stay. The ICU and 30-day mortality were, respectively, 29.1 and 53.1% in the withholding group and 82.2% and 93.1% in the withdrawal group. LST was less frequently limited in eastern and southern European countries than in northern Europe. The patient-independent factors associated with LST limitation were: acute ICU admission (OR 5.77, 95% CI 4.32–7.7), Clinical Frailty Scale (CFS) score (OR 2.08, 95% CI 1.78–2.42), increased age (each 5 years of increase in age had a OR of 1.22 (95% CI 1.12–1.34) and SOFA score [OR of 1.07 (95% CI 1.05–1.09 per point)]. The frequency of LST limitation was higher in countries with high GDP and was lower in religious countries.ConclusionsThe most important patient variables associated with the instigation of LST limitation were acute admission, frailty, age, admission SOFA score and country.Trial registrationClinicalTrials.gov (ID: NTC03134807).

The mitochondrial biogenesis and energy expenditure regulator, PGC-1α, has been previously reported to be induced in the white adipose tissue (WAT) and liver of mice overexpressing spermidine/spermine N 1 -acetyltransferase (SSAT). The activation of PGC-1α in these mouse lines leads to increased number of mitochondria, improved glucose homeostasis, reduced WAT mass and elevated basal metabolic rate. The constant activation of polyamine catabolism produces a futile cycle that greatly reduces the ATP pools and induces 5′-AMP-activated protein kinase (AMPK), which in turn activates PGC-1α in WAT. In this study, we have investigated the effects of activated polyamine catabolism on the glucose and energy metabolisms when targeted to specific tissues. For that we used a mouse line overexpressing SSAT under the endogenous SSAT promoter, an inducible SSAT overexpressing mouse model using the metallothionein I promoter (MT-SSAT), and a mouse model with WAT-specific SSAT overexpression (aP2-SSAT). The results demonstrated that WAT-specific SSAT overexpression was sufficient to increase the number of mitochondria, reduce WAT mass and protect the mice from high-fat diet-induced obesity. However, the improvement in the glucose homeostasis is achieved only when polyamine catabolism is enhanced at the same time in the liver and skeletal muscle. Our results suggest that the tissue-specific targeting of activated polyamine catabolism may reveal new possibilities for the development of drugs boosting mitochondrial metabolism and eventually for treatment of obesity and type 2 diabetes.

Background: Data on high flow nasal oxygenation (HFNO) efficacy in hypoxia prevention in transcatheter aortic valve replacement (TAVR) are conflictive. We aimed to determine the benefit of HFNO in preventing the occurrence of desaturations during TAVR. Methods: An investigator-initiated, proof of concept, single-centre, randomised, and controlled trial on 132 adult patients who were scheduled to undergo transfemoral TAVR was conducted. Patients were randomised (1:1) to HFNO (H-group) with a flow rate of 50 L min−1 and FiO2 0.6 or standard of care oxygen therapy (S-group). The primary endpoint was the number of patients with a desaturation episode (SpO2 < 93%) for >10 s during TAVR. Secondary outcomes included arterial partial pressure of oxygen (pO2) 45 min from sedation start and changes in glomerular filtration rate from baseline to 12 h post-procedure. Results: Between 23 November and 24 July, a per-protocol analysis was performed in a total of 125 patients (H-group n = 64; S- group n = 61; 49 females). The number of patients with any desaturation episode was significantly lower in the H-group [13/64 (20%, 95% CI: 12–32%)] than in the S-group [31/61 (51%, 95% CI: 39–63%), RR: 0.39 (95%CI: 0.23–0.68)]. At 45 min, mean (SD) pO2 was higher in the H-group (24(9.8) kPa vs. 16.7(7.5) kPa; p < 0.005). A significant improvement in delta median (IQR) difference on glomerular filtration rate was observed in the H-group [1.6(−1–7.9) mL min−1 1.73 m−2] with respect to the S-group [0.2(−6.1–3.1) mL min−1 1.73 m−2; p-value: 0.013]. Conclusions: This trial demonstrated that HFNO provides a better oxygenation pattern than standard oxygen therapy during TAVR. Larger studies focusing on long-term clinical outcomes are warranted to evaluate the benefit of HFNO during sedation for TAVR procedures.

This paper presents a live field experience of creating an isolated microgrid for the Expoelectric fair during 2018 and 2019. The islanded microgrid comprises a Master Inverter with grid-forming capabilities and fault management. The Master Inverter and stationary batteries, and EVs with V2G capabilities provide storage. A PV generation system supplies the microgrid. The loads are the fair booths, mainly lighting and chargers for personal mobility vehicles. All the equipment used in the experimental microgrid is from different manufacturers. The operation and control of the islanded microgrid are based on the VDE-AR-N-4105 standard. The paper also presents the operation of the Master Inverter during faults. The live field experience shows that the proposed operation method is valid for operating different converters from different manufacturers without needing any communication layer between them. The experimental results also show that faults can be handled correctly by the Master Inverter to operate the entire microgrid safely. In conclusion, islanded microgrids based on power electronics are feasible to replace diesel generators in faires, conventions or temporary events.

Microgrid integration and fault protection in complex network scenarios is a coming challenge to be faced with new strategies and solutions. In this context of increasing complexity, this paper describes two specific overload control strategies for four-wire inverters integrated in low voltage four-wire alternating current (AC) microgrids. The control of grid-tied microgrid inverters has been widely studied in the past and mainly focused on the use of droop control, which hugely constrains the time response during grid-disconnected operation. Taking into account the previous knowledge and experience about this subject, the main contribution of these two proposals regards providing fault current limitation in both operation modes, over-load capability skills in grid-connected operation and sinusoidal short-circuit proof in grid-disconnected operation. In the complex operation scenarios mentioned above, a hybrid combination of AC droop control based on dynamic phasors with varying virtual resistance, and voltage/frequency master voltage control for grid-(dis)connected operation modes are adopted as the mechanism to enhance time response. The two proposals described in the present document are validated by means of simulations using Matlab/Simulink and real experimental results obtained from CENER (The National Renewable Energy Centre) experimental ATENEA four-wire AC microgrid, obtaining time responses in the order of two-three grid cycles for all cases.