Explore the vast range of titles available.

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.

Transcatheter Aortic Valve Implantation (TAVI) has emerged as a less invasive alternative to surgical aortic valve replacement, especially for high-risk patients. While TAVI is expected to improve symptoms and functional status, clinical recovery is often heterogeneous, and subjective assessments may not fully capture the degree of improvement. To our knowledge, the changes in functional capacity following TAVI have not been well explored using cardiopulmonary exercise testing (CPET).The study aims to characterise mid-term changes in exercise tolerance after TAVI and identify clinical and functional predictors of improvement in exercise capacity and complications after TAVI. A total of 161 patients with severe aortic stenosis scheduled for TAVI will be prospectively enrolled across three expert centres. Each will undergo clinical assessment and incremental CPET within two weeks before and four to six weeks after the procedure. The primary outcome is a change in VO₂ peak and VO₂ at the anaerobic threshold. Secondary outcomes include exploratory associations between baseline characteristics and observed changes in functional capacity, quality of life and complications. The bioethics committee of the Hospital Clínic de Barcelona, Spain, approved this protocol (HCB/2024/0782). All the participating centres obtained local approval prior to patient recruitment. The findings will be published in a peer-reviewed journal and submitted to relevant conferences. ClinicalTrials.gov NCT06833762 (registered 10th of March 2025).

Background High-concentration-capsaicin-patches (Qutenza®) have been put on the market as a treatment for peripheral neuropathic pain. A minimum infrastructure and a determinate skill set for its application are required. Our aim was to assess the feasibility of treatment with high-concentration-capsaicin-patches in clinical practice in a variety of refractory peripheral neuropathic pain syndromes in non-diabetic patients. Methods Observational, prospective, single-center study of patients attended to in the Pain Unit of a tertiary hospital, ≥18 year-old non-responders to multimodal analgesia of both genders. The feasibility for the application of capsaicin patch in clinical practice was evaluated by means of the number of patients controlled per day when this one was applied and by means of the times used for patch application. Results Between October 2010 and September 2011, 20 consecutive non-diabetic patients (7 males, 13 females) with different diagnoses of refractory peripheral neuropathic pain syndromes, with a median (range) age of 60 (33–88) years-old were treated with a single patch application. The median (range) number of patients monitored per day was not modified when the capsaicin patch was applied [27 (26–29)] in comparison with it was not applied [28 (26–30)]. The median (range) total time to determine and mark the painful area was 9 (6–15) minutes and of patch application was 60 (58–65) minutes. No important adverse reactions were observed. Conclusion High-concentration-capsaicin-patch treatment was feasible in our unit for the treatment of a population with refractory peripheral neuropathic pain. The routine of our unit was not affected by its use.

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.