BACKGROUND: Skeletal muscle alterations are associated with higher mortality and morbidity in patients with liver cirrhosis. Assessing these changes seems to be a promising method for identifying patients at a high risk of poor outcomes following liver transplantation (LT). This is particularly important given the current global shortage of organ donors. However, evidence of the impact of these alterations on the prognosis of patients undergoing LT is inconclusive. The aim of our prospective study was to evaluate the impact of skeletal muscle changes, reflected in sarcopenia, myosteatosis and metabolic changes in the calf muscles, on perioperative outcomes and long-term survival after LT. We also sought to determine the posttransplant evolution of the resting muscle metabolism. METHODS: We examined 134 adult LT candidates. Of these, 105 underwent LT. Sarcopenia and myosteatosis were diagnosed by measuring the skeletal muscle index and mean psoas muscle radiation attenuation, respectively, which were obtained from computed tomography (CT) scans taken during pretransplant assessment. Additionally, patients underwent 31P MR spectroscopy (MRS) of the calf muscles at rest before LT and 6, 12 and 24 months thereafter. The median follow-up was 6 years. RESULTS: Patients with abnormal 31P MRS results and CT-diagnosed myosteatosis prior to LT had significantly worse long-term survival after LT (hazard ratio (HR), 3.36; 95% confidence interval (CI), 1.48-7.60; p = 0.0021 and HR, 2.58; 95% CI, 1.06-6.29; p = 0.03, respectively). Multivariable analysis showed that abnormal 31P MR spectra (HR, 3.40; 95% CI, 1.50-7.71; p = 0.003) were a better predictor of worse long-term survival after LT than myosteatosis (HR, 2.78; 95% CI, 1.14-6.78; p = 0.025). Patients with abnormal 31P MR spectra had higher blood loss during LT (p = 0.038), required a higher number of red blood cell transfusions (p = 0.006) and stayed longer in ICU (p = 0.041) and hospital (p = 0.007). Myosteatosis was associated with more revision surgeries following LT (p = 0.038) and a higher number of received red blood cell transfusion units (p = 0.002). Sarcopenia had no significant effect on posttransplant patient survival. An improvement in the resting metabolism of the calf muscles was observed at 12 and 24 months after LT. CONCLUSIONS: Abnormal 31P MRS results of calf muscles were superior to CT-based diagnosis of myosteatosis and sarcopenia in predicting perioperative complications and long-term survival after LT. Resting muscle metabolism normalized 1 year after LT in most recipients.
- MeSH
- dospělí MeSH
- kosterní svaly * diagnostické zobrazování metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie * metody MeSH
- počítačová rentgenová tomografie * metody MeSH
- prognóza MeSH
- prospektivní studie MeSH
- sarkopenie etiologie metabolismus MeSH
- senioři MeSH
- transplantace jater * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: This meta-analysis aimed to compare the efficacy of preservation of the intercostobrachial nerve (ICBN) versus its dissection for patients who underwent breast surgery. METHODS: The authors searched Web of Science, PubMed, Cochrane CENTRAL, and Scopus from inception until March 2023. Records were screened for eligible studies, and all relevant outcomes were pooled as an odds ratio (OR) with the corresponding 95% CI in the meta-analysis models using RevMan version 5.4. RESULTS: These results from 11 studies (1021 patients) favored preservation of the ICBN over its dissection in terms of anaesthesia and hypaesthesia [OR 0.50, (95% CI, 0.31-0.82); P = 0.006] and [OR 0.33, (95% CI, 0.16-0.68); P = 0.003], respectively. Whereas the overall effect favored ICBN dissection over preservation in the case of hyperaesthesia [OR 4.34, (95% CI, 1.43-13.15); P = 0.01]. Conversely, no significant variance was detected between the two groups in terms of pain [OR 0.68, (95% CI, 0.28-1.61) P = 0.38], paraesthesia [OR 0.88, (95% CI, 0.49-1.60); P = 0.68], and analgesia [OR 1.46, (95% CI, 0.05-45.69); P = 0.83]. CONCLUSION: This meta-analysis revealed that the preservation of the ICBN has a significant effect on the disturbance of sensory parameters of hypaesthesia and anaesthesia when compared to its dissection. Further studies with larger sample sizes are recommended to precisely compare both techniques on a wider range of parameters.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE: By exposing mice carrying a deletion of NADPH oxidase isoform 4, NOX4, specifically in pancreatic β cells (βNOX4-/-) to nutrient excess stimulated by a high-fat diet (HFD), this study aimed to elucidate the role of β-cell redox status in the development of meta-inflammation within the diabetic phenotype. METHODS: The authors performed basic phenotyping of βNOX4-/- mice on HFD involving insulin and glycemic analyses, histochemistry of adipocytes, indirect calorimetry, and cytokine analyses. To characterize local inflammation, the study used caspase-1 activity assay, interleukin-1β immunochemistry, and real-time polymerase chain reaction during coculturing of β cells with macrophages. RESULTS: The phenotype of βNOX4-/- mice on HFD was not associated with hyperinsulinemia and hyperglycemia but showed accumulation of excessive lipids in epididymal fat and β cells. Surprisingly, mice showed significantly reduced systemic inflammation. Decreased interleukin-1β protein levels and downregulated NLRP3-inflammasome activity were observed on chronic glucose overload in βNOX4-/- isolated islets and NOX4-silenced INS1-E cells resulting in attenuated proinflammatory polarization of macrophages/monocytes in vitro and in situ and reduced local islet inflammation. CONCLUSIONS: Experimental evidence suggests that NOX4 pro-oxidant activity in β cells is involved in NLRP3-inflammasome activation during chronic nutrient overload and participates in local inflammatory signaling and perhaps toward peripheral tissues, contributing to a diabetic inflammatory phenotype.
INTRODUCTION: Thoracic aorta false aneurysms (TAFA) are unexplored complications after cardiac surgery associated with significant morbidity and mortality. Therefore, the purpose of this study was to examine the clinical profiles, surgical techniques, and operative outcomes, of patients treated for TAFA at a single institution. METHODS: From 1996 to 2022, 112 patients were treated for aortic pseudoaneurysm (mean age 55 ± 14 years, 78 patients were male). In the majority of the patients (90%) TAFA developed after previous cardiovascular surgery, the most common diagnosis and surgical procedure preceding the TAFA development was an aortic dissection (52%) and Bentall procedure (47%). In the rest of the cohort, the leading cause was trauma. RESULTS: Sixty-one percent of patients were indicated for reintervention (surgical reoperation, endoluminal graft implantation, septal occluder implantation, coil embolization, or a combination of procedures). Overall, 52 patients had undergone cardiac reoperation. TAFA was resected and the aorta was repaired in 55% or replaced in 45%. Operative mortality was 5.7%. In postoperative follow-up, a hypoechogenic lesion encircling aortic prosthesis was present in 94%, therefore it was determined as a negative prognostic factor. The mean follow-up was 13.2 ± 19.4 years. CONCLUSION: Although there is no specific approach how to prevent TAFA development, maintaining normal blood pressure and regular follow-up should be applied. More frequent follow-ups should be performed in patients with a hypoechogenic lesion encircling and aortic prosthesis. Early detection during long-term postoperative follow-up, an individually tailored approach of a multidisciplinary team is necessary for favorable treatment outcomes.
- MeSH
- aneurysma hrudní aorty * chirurgie MeSH
- aorta thoracica chirurgie diagnostické zobrazování MeSH
- časové faktory MeSH
- cévy - implantace protéz škodlivé účinky MeSH
- dospělí MeSH
- endovaskulární výkony škodlivé účinky MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nepravé aneurysma * chirurgie etiologie diagnostické zobrazování terapie MeSH
- pooperační komplikace etiologie chirurgie MeSH
- reoperace MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Proteins from the Bcl-2 family play an essential role in the regulation of apoptosis. However, they also possess cell death-unrelated activities that are less well understood. This prompted us to study apoptosis-unrelated activities of the Bax and Bak, pro-apoptotic members of the Bcl-2 family. We prepared Bax/Bak-deficient human cancer cells of different origin and found that while respiration in the glioblastoma U87 Bax/Bak-deficient cells was greatly enhanced, respiration of Bax/Bak-deficient B lymphoma HBL-2 cells was slightly suppressed. Bax/Bak-deficient U87 cells also proliferated faster in culture, formed tumours more rapidly in mice, and showed modulation of metabolism with a considerably increased NAD+/NADH ratio. Follow-up analyses documented increased/decreased expression of mitochondria-encoded subunits of respiratory complexes and stabilization/destabilization of the mitochondrial transcription elongation factor TEFM in Bax/Bak-deficient U87 and HBL-2 cells, respectively. TEFM downregulation using shRNAs attenuated mitochondrial respiration in Bax/Bak-deficient U87 as well as in parental HBL-2 cells. We propose that (post)translational regulation of TEFM levels in Bax/Bak-deficient cells modulates levels of subunits of mitochondrial respiratory complexes that, in turn, contribute to respiration and the accompanying changes in metabolism and proliferation in these cells.
- MeSH
- apoptóza * genetika MeSH
- dýchání MeSH
- lidé MeSH
- mitochondrie genetika metabolismus MeSH
- myši MeSH
- protein Bak * genetika metabolismus MeSH
- protein X asociovaný s bcl-2 genetika metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Semantic and short-term episodic memory are impaired in some brain disorders including Alzheimer's disease. OBJECTIVE: Development and validation of an almost self-administered, but cognitively demanding four-minute test identifying very mild cognitive impairment (vMCI). METHODS: The innovative hedgehog PICture Naming and Immediate Recall (PICNIR) consisted of two parts. The first task was to write down the names of 20 black-and-white pictures to evaluate long-term semantic memory and language. The second task involves immediate recall and writing the names of as many previously named pictures as possible in one minute. The PICNIR is assessed using the number of naming errors (NE) and correctly recalled picture names (PICR). The PICNIR and a neuropsychological battery were administered to 190 elderly individuals living independently in the community. They were divided into those with vMCI (n = 43 with Montreal Cognitive Assessment (MoCA) 24 ± 3 points) and sociodemographically matched cognitively normal (CN) individuals (n = 147 with MoCA 26 ± 3). Both subgroups had predicted mean Mini-Mental State Examination scores of 28-29 points. RESULTS: Compared to CN, vMCI participants made more NE (0.3 ± 0.6 versus 0.6 ± 0.9; p = 0.02) and recalled fewer PICR (8.9 ± 2.2 versus 6.8 ± 2.2; p < 0.000001). Discriminative validity was satisfactory using the area under the ROC curve (AUC): 0.76 for PICR, 0.74 for MoCA, 0.67 for MoCA-five-word recall, and 0.59 for NE. The AUCs of PICR and MoCA were comparable and larger than those of MoCA five-point recall or NE. Logical Memory scores, RAVLT scores, Digit symbol, and animal fluency correlated with PICR. CONCLUSIONS: The picture-based PICNIR is an ultra-brief, sensitive cognitive test valid for assessing very mild cognitive impairment. Its effectiveness should be validated for other languages and cultures.
- MeSH
- epizodická paměť * MeSH
- kognitivní dysfunkce * diagnóza psychologie MeSH
- krátkodobá paměť fyziologie MeSH
- lidé MeSH
- neuropsychologické testy * statistika a číselné údaje MeSH
- reprodukovatelnost výsledků MeSH
- rozpomínání * fyziologie MeSH
- sémantika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- testy pro posouzení mentálních funkcí a demence statistika a číselné údaje MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. METHODS: Patients aged ≥ 18 years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8 Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. RESULTS: Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0 months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. CONCLUSION: SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. TRIAL REGISTRATION: EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.
- Publikační typ
- časopisecké články MeSH
AIM: To compare open-source AndroidAPS (AAPS) and commercially available Control-IQ (CIQ) automated insulin delivery (AID) systems in a prospective, open-label, single-arm clinical trial. METHODS: Adults with type 1 diabetes who had been using AAPS by their own decision entered the first 3-month AAPS phase then were switched to CIQ for 3 months. The results of this treatment were compared with those after the 3-month AAPS phase. The primary endpoint was the change in time in range (% TIR; 70-80 mg/dL). RESULTS: Twenty-five people with diabetes (mean age 34.32 ± 11.07 years; HbA1c 6.4% ± 3%) participated in this study. CIQ was comparable with AAPS in achieving TIR (85.72% ± 7.64% vs. 84.24% ± 8.46%; P = .12). Similarly, there were no differences in percentage time above range (> 180 and > 250 mg/dL), mean sensor glucose (130.3 ± 13.9 vs. 128.3 ± 16.9 mg/dL; P = .21) or HbA1c (6.3% ± 2.1% vs. 6.4% ± 3.1%; P = .59). Percentage time below range (< 70 and < 54 mg/dL) was significantly lower using CIQ than AAPS. Even although participants were mostly satisfied with CIQ (63.6% mostly agreed, 9.1% strongly agreed), they did not plan to switch to CIQ. CONCLUSIONS: The CODIAC study is the first prospective study investigating the switch between open-source and commercially available AID systems. CIQ and AAPS were comparable in achieving TIR. However, hypoglycaemia was significantly lower with CIQ.
- MeSH
- diabetes mellitus 1. typu * farmakoterapie MeSH
- dospělí MeSH
- glykovaný hemoglobin MeSH
- hypoglykemika terapeutické užití MeSH
- inzulin terapeutické užití MeSH
- inzulinové infuzní systémy MeSH
- inzuliny * MeSH
- krevní glukóza MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- prospektivní studie MeSH
- selfmonitoring glykemie metody MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health. METHODS: We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells. RESULTS: Glucose stimulation significantly increases ROS levels in β-cells, leading to targeted reversible oxidation of proteins involved in key metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum (ER), and insulin secretion. Furthermore, the glucose-induced increase in reversible cysteine oxidation correlates with the presence of other post-translational modifications, including acetylation and phosphorylation. CONCLUSIONS: Proper functioning of pancreatic β-cell metabolism relies on fine-tuned regulation, achieved through a sophisticated system of diverse post-translational modifications that modulate protein functions. Our findings demonstrate that glucose induces the production of ROS in pancreatic β-cells, leading to targeted reversible oxidative modifications of proteins. Furthermore, protein activity is modulated by acetylation and phosphorylation, highlighting the complexity of the regulatory mechanisms in β-cell function.
- MeSH
- beta-buňky * metabolismus účinky léků MeSH
- fyziologická adaptace fyziologie MeSH
- glukosa * metabolismus MeSH
- lidé MeSH
- myši MeSH
- oxidace-redukce * MeSH
- posttranslační úpravy proteinů MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- sekrece inzulinu účinky léků fyziologie MeSH
- signální transdukce * fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.
- MeSH
- akutní lymfatická leukemie farmakoterapie metabolismus patologie MeSH
- antitumorózní látky farmakologie MeSH
- asparaginasa * farmakologie metabolismus MeSH
- citrátový cyklus účinky léků MeSH
- glutamin metabolismus MeSH
- glutathion * metabolismus MeSH
- kyselina glutamová * metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
