Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression ...to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.
Aims
A higher
SGLT1
and
GLUT2
gene expression was shown in the intestine of subjects with type 2 diabetes, while no data have been reported in type 1 diabetes (T1D). The purpose of our study was to ...evaluate the expression of glucose transporters in duodenal mucosa of subjects with T1D, compared to healthy controls (CTRL) and to patients with celiac disease (CD), as gut inflammatory disease control group.
Materials and methods
Gene expression of
GLUT1
,
GLUT2
,
SGLT1
and
SGLT2
was quantified on duodenal mucosa biopsies of subjects with T1D (
n
= 19), CD (
n
= 16), T1D and CD (
n
= 6) and CTRL (
n
= 12), recruited at San Raffaele Hospital (Milan, Italy), between 2009 and 2018.
SGLT2
expression was further evaluated by immunohistochemical and immunofluorescence staining.
Results
The expression of all four glucose transporters was detected in duodenal mucosa of all groups. A reduced
GLUT2
,
SGLT1
and
SGLT2
expression was observed in CD in comparison with T1D and CTRL, as expected;
GLUT1
was significantly more expressed in T1D compared to CTRL.
SGLT2
expression was quantified at much lower levels than other transporters, with no differences between groups.
SGLT2
expression was confirmed by immunohistochemistry in a restricted number of enterocytes lining in the mucosa of intestinal villi, also shown on immunofluorescence.
Conclusions
Our results show that glucose transporters expression in duodenal mucosa of subjects with T1D, except an increased
GLUT1
, is not different from that observed in healthy controls. The expression of
SGLT2
in human duodenal mucosa, although at low intensity, represents a novel finding.
The worldwide spread of a new coronavirus (SARS-CoV-2) since December 2019 has posed a severe threat to individuals' well-being. While the world at large is waiting that the released vaccines ...immunize most citizens, public health experts suggest that, in the meantime, it is only through behavior change that the spread of COVID-19 can be controlled. Importantly, the required behaviors are aimed not only at safeguarding one's own health. Instead, individuals are asked to adapt their behaviors to protect the community at large. This raises the question of which social concerns and moral principles make people willing to do so. We considered in 23 countries (N = 6948) individuals' willingness to engage in prescribed and discretionary behaviors, as well as country-level and individual-level factors that might drive such behavioral intentions. Results from multilevel multiple regressions, with country as the nesting variable, showed that publicized number of infections were not significantly related to individual intentions to comply with the prescribed measures and intentions to engage in discretionary prosocial behaviors. Instead, psychological differences in terms of trust in government, citizens, and in particular toward science predicted individuals' behavioral intentions across countries. The more people endorsed moral principles of fairness and care (vs. loyalty and authority), the more they were inclined to report trust in science, which, in turn, statistically predicted prescribed and discretionary behavioral intentions. Results have implications for the type of intervention and public communication strategies that should be most effective to induce the behavioral changes that are needed to control the COVID-19 outbreak.
Ductal patency of preterm infants is potentially associated with long term morbidities related to either pulmonary overflow or systemic steal. When an interventional closure is needed, it can be ...achieved with either surgical ligation or a catheter-based approach.Transcatheter PDA closure is among the safest of interventional cardiac procedures and it is the first choice for ductal closure in adults, children, and infants weighing more than 6 kg. In preterm and very low birth weight infants, it is increasingly becoming a valid and safe alternative to ligation, especially for the high success rate and the minor invasiveness and side effects. Nevertheless, being it performed at increasingly lower weights and gestational ages, hemodynamic complications are possible events to be foreseen.Procedural steps, timing, results, possible complications and available monitoring systems, as well as future outlooks are here discussed.
The wild-type protein p53 plays a key role in preventing the formation of neoplasms by controlling cell growth. However, in more than a half of all cancers, the
gene has missense mutations that ...appear during tumorigenesis. In most cases, the mutated gene encodes a full-length protein with the substitution of a single amino acid, resulting in structural and functional changes and acquiring an oncogenic role. This dual role of the wild-type protein and the mutated isoforms is also evident in the regulation of the redox state of the cell, with antioxidant and prooxidant functions, respectively. In this review, we introduce a new concept of the p53 protein by discussing its sensitivity to the cellular redox state. In particular, we focus on the discussion of structural and functional changes following post-translational modifications of redox-sensitive cysteine residues, which are also responsible for interacting with zinc ions for proper structural folding. We will also discuss therapeutic opportunities using small molecules targeting cysteines capable of modifying the structure and function of the p53 mutant isoforms in view of possible anticancer therapies for patients possessing the mutation in the
gene.
BackgroundThe TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy.MethodsA panel of wild-type and ...mutant p53 cancer cell lines of different tissues, including pancreas, breast, skin, and lung were used, as well as chronic lymphocytic leukemia (CLL) patients with different TP53 gene status. The effects of mutant p53 were evaluated by confocal microscopy, reactive oxygen species production assay, immunoblotting, and quantitative reverse transcription polymerase chain reaction after cellular transfection.ResultsWe demonstrate that oncogenic mutant p53 isoforms are able to inhibit SESN1 expression and consequently the amount of SESN1/AMPK complex, resulting in the downregulation of the AMPK/PGC-1α/UCP2 axis and mitochondrial O2ˉ· production. We also show a correlation between the decrease of reduced thiols with a poorer clinical outcome of CLL patients bearing mutant TP53 gene. The restoration of the mitochondrial uncoupling protein 2 (UCP2) expression, as well as the addition of the radical scavenger N-acetyl-l-cysteine, reversed the oncogenic effects of mutant p53 as cellular hyper-proliferation, antiapoptotic effect, and resistance to drugs.ConclusionsThe inhibition of the SESN1/AMPK/PGC-1α/UCP2 axis contributes to the pro-oxidant and oncogenic effects of mutant p53, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing mutant TP53 gene.
The Occlutech Atrial Flow Regulator (AFR) is a self-expandable double-disc nitinol device with a central fenestration. Its use has been approved in the adult population with heart failure and ...described for pulmonary hypertension (PH). Only case reports and small series have been published about its use in the paediatric population and for congenital heart disease (CHD).
The authors sought to investigate the feasibility, safety, and short-term follow-up of AFR implantation in patients with CHD or children with PH or cardiomyopathy.
This is a multicenter retrospective study involving 10 centers worldwide. Patients of any age with CHD or patients aged < 18 years with PH or cardiomyopathy needing AFR implantation were included.
A total of 40 patients underwent AFR implantation. The median age of the population at the time of the procedure was 58.5 months (IQR: 31.5-142.5) and the median weight was 17 kg (IQR: 10-46). A total of 26 (65.0%) patients had CHD, nine (22.5%) children, a cardiomyopathy, and five (12.5%), a structurally normal heart. The implantation success rate was 100%. There were two early and one late device thrombosis. Two patients (5.0%) with dilated cardiomyopathy on extracorporeal membrane oxygenator (ECMO) died during the hospital stay. At a median follow-up of 330 days (IQR: 125-593), 37 (92.5%) patients were alive. At follow-up, 20 patients improved their New York Heart Association (NYHA) class, 12 patients did not change their NYHA class, and one patient with idiopathic PH worsened.
AFR implantation in patients with CHD and children with severe PH or cardiomyopathy is promising and seems to have beneficial effects at short-term follow-up.
The identification of patients who can benefit the most from the available preventive treatments is important in chronic migraine. We explored the rate of excellent responders to onabotulinumtoxinA ...in a multicenter European study and explored the predictors of such response, according to different definitions. A pooled analysis on chronic migraineurs treated with onabotulinumtoxinA and followed-up for, at least, 9 months was performed. Excellent responders were defined either as patients with a ≥75% decrease in monthly headache days (percent-based excellent responders) or as patients with <4 monthly headache days (frequency-based excellent responders). The characteristics of excellent responders at the baseline were compared with the ones of patients with a <30% decrease in monthly headache days. Percent-based excellent responders represented about 10% of the sample, whilst frequency-based excellent responders were about 5% of the sample. Compared with non-responders, percent-based excellent responders had a higher prevalence of medication overuse and a higher excellent response rate even after the 1st and the 2nd injection. Females were less like to be frequency-based excellent responders. Chronic migraine sufferers without medication overuse and of female sex may find fewer benefits with onabotulinumtoxinA. Additionally, the excellent response status is identifiable after the first cycle.
The 759 cases of brain death declaration (BDD Italian law, 6 hours of observation time) that occurred in 190 Italian intensive care units (ICUs) between May and September 2012 were studied to ...quantify carbapenem‐resistant gram‐negative bacteria (CR‐GN) isolated in organ donors, to evaluate adherence to national screening guidelines, and to identify risk factors for CR‐GN isolation. Mandatory blood, bronchoalveolar lavage, and urine cultures were performed on the BDD day in 99% of used donors. Because results were rarely made available before transplant, >20% of transplants were performed before obtaining any microbiological information, and organs from 15 of 22 CR‐GN cases were used. Two (lung–liver) of the 37 recipients died, likely because of donor‐derived early CR‐GN sepsis. ICU stay >3 days (odds ratio OR = 7.49, P = .004), fever (OR = 3.11, P = .04), age <60 years (OR = 2.80, P = .06), and positive ICU epidemiology (OR = 8.77, P = .07) were associated with CR‐GN isolation. An association between single ICU and risk of CR‐GN was observed, as a result of differences across ICUs (ICC = 29%; 95% confidence interval CI 6.5%‐72%) probably related to inadequate practices of infection control. Continuous education aimed at implementing priority actions, including stewardship programs for a rational use of antimicrobials, is a priority in healthcare systems and transplant networks. Improved awareness among ICU personnel regarding the importance of early CR‐GN detection and timely alert systems might facilitate decisions regarding organ suitability and eventually save recipient lives.
In this national study, the authors evaluate the risk factors for carbapenem‐resistant, gram‐negative bacteria isolation in brain dead organ donors and possibly related recipient deaths, suggesting that tailored surveillance cultures, timely information, and alert systems based on critical care personnel education and transplant network organization might facilitate and improve decisions regarding organ suitability.
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