26 research outputs found
O2 delivery and CO2 production during cardiopulmonary bypass as determinants of acute kidney injury: time for a goal-directed perfusion management?
Get PDFIntroduction: Acute kidney injury (AKI) is common after cardiac operations. There are different risk factors or determinants of AKI, and some are related to cardiopulmonary bypass (CPB). In this study, we explored the association between metabolic parameters (oxygen delivery (DO(2)) and carbon dioxide production (VCO(2))) during CPB with postoperative AKI.
Methods: We conducted a retrospective analysis of prospectively collected data at two different institutions. The study population included 359 adult patients. The DO(2) and VCO(2) levels of each patient were monitored during CPB. Outcome variables were related to kidney function (peak postoperative serum creatinine increase and AKI stage 1 or 2). The experimental hypothesis was that nadir DO(2) values and nadir DO(2)/VCO(2) ratios during CPB would be independent predictors of AKI. Multivariable logistic regression models were built to detect the independent predictors of AKI and any kind of kidney function damage.
Results: A nadir DO2 level < 262 mL/minute/m(2) and a nadir DO(2)/VCO(2) ratio < 5.3 were independently associated with AKI within a model including EuroSCORE and CPB duration. Patients with nadir DO(2) levels and nadir DO(2)/VCO(2) ratios below the identified cutoff values during CPB had a significantly higher rate of AKI stage 2 (odds ratios 3.1 and 2.9, respectively). The negative predictive power of both variables exceeded 90%. The most accurate predictor of AKI stage 2 postoperative status was the nadir DO(2) level. Conclusions: The nadir DO(2) level during CPB is independently associated with postoperative AKI. The measurement of VCO(2)-related variables does not add accuracy to the AKI prediction. Since DO(2) during CPB is a modifiable factor (through pump flow adjustments), this study generates the hypothesis that goal-directed perfusion management aimed at maintaining the DO(2) level above the identified critical value might limit the incidence of postoperative AKI
“The whole thing is beyond stress”: Family perspectives on the experience of hospitalisation through to discharge for individuals with severe learning disabilities and complex needs
Get PDF© 2024 The Authors. British Journal of Learning Disabilities published by John Wiley & Sons Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background People with severe learning disabilities and complex needs are more likely to experience delayed discharge from hospital; however, there is little research into their experience in hospital and as they move out as part of the Transforming Care Programme. Methods Six family members of people with complex needs who had moved out of hospital took part in four focus groups co-facilitated with an expert-by-experience consultant. Participants' relatives had hospital admissions that ranged from 6 weeks to 11 years. Transcripts were analysed using reflexive thematic analysis. Additional reflections are included from an expert-by-experience consultant to capture their unique perspective. Results Family members reported stories of abuse in hospital and parallel experiences of institutionalisation and trauma, resulting in long-lasting impacts on themselves and their relative. Family members felt let down and undervalued by professionals. They described relief when their relatives moved out of hospital, but there were on-going difficulties accessing the right support in the community and so stability felt fragile. Conclusions Key recommendations to support community living include respecting family members' expertise, improving partnership working and offering psychological support for family members and people with complex needs post-discharge.Peer reviewe
Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction
Get PDFEndotoxemia; Inflammation; Mitochondrial functionEndotoxemia; Inflamación; Función mitocondrialEndotoxèmia; Inflamació; Funció mitocondrialBackground and Aims
The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD.
Methods
The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice.
Results
In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity.
Conclusion
Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis.Open access funding provided by Lund University. This study was supported by grants from the Marianne and Marcus Wallenberg Foundation the Swedish Heart and Lung Foundation, the Swedish Research Council, the Bundy Academy foundation at Lund University, Skåne Region Research Funds, Malmö University Hospital Funds, the Crafoord Foundation, the Royal Physiographic Society in Lund, Swedish Research Council, Östergotland Region Research Funds, and the Ministry of Research and Education of Romania (PNRR-C9/I8-CF148)
HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness
Get PDFHigh spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified HNRNPM as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and back-splicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching-antisense-oligonucleotides (SSOs) was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors
