Effect of small dose esketamine on perioperative neurocognitive disorder and postoperative depressive symptoms in elderly patients undergoing major elective noncardiac surgery for malignant tumors: A randomized clinical trial.

BACKGROUND: Perioperative neurocognitive disorder and postoperative depressive symptoms are significant complications after surgery. Studies have indicated that esketamine possesses neuroprotective and antidepressant qualities. METHODS: This trial included 209 patients aged 60 to 86 years undergoing tumor resection who received esketamine (Group E) or not (Group C) during and after surgery. In group E, patients were given an intravenous dose of 0.5 mg/kg of esketamine 10 minutes after induction of general anaesthesia. In addition, esketamine (2 mg/kg) in combination with sufentanil was used for PCIA during 48 hours postoperatively. On the other hand, saline was used as a substitute for esketamine in group C. Cognitive function was evaluated using neuropsychological tests and telephone interview for cognitive status-modified, and symptoms of depression were assessed using Hamilton Depression Rating Scale 17. RESULTS: Compared to Group C, patients in Group E exhibited lower rates of depressive symptoms at 3, 7, and 90 days post-surgery (53.9% vs 67.7%, 26.3% vs 47.9%, and 13.3% vs 28.4%). Group E also showed decreased time for Trail Making Test on days 7 and 90. However, there were no significant differences in the incidence of delirium 1 to 5 days post-surgery or cognitive impairment 90 days post-surgery between the 2 groups (12.1% vs 10.9% and 8.4% vs 9.7%). CONCLUSIONS: Intraoperative low-dose esketamine and postoperative low-dose esketamine combined with sufentanil for patient-controlled intravenous analgesia has been shown to improve postoperative analgesia, alleviate postoperative depressive symptoms, and aid in the recovery of social executive ability. However, this approach did not reduce the incidence of postoperative delirium or postoperative cognitive dysfunction.

Transforming growth factor-ß1 is associated with inflammatory resolution via regulating macrophage polarization in lung injury model mice.

OBJECTIVE: Ventilation is the main respiratory support therapy for acute respiratory distress syndrome, which triggers acute lung injury (ALI). Macrophage polarization is vital for the resolution of inflammation and tissue injury. We hypothesized that transforming growth factor (TGF)-ß1 may attenuate inflammation and ventilator-induced ALI by promoting M2 macrophage polarization. METHODS: C57BL/6 mice received 4-hour ventilation and extubation to observe the resolution of lung injury and inflammation. Lung vascular permeability, inflammation, and histological changes in the lungs were evaluated by bronchoalveolar lavage analysis, enzyme linked immunosorbent assay, hematoxylin and eosin staining, as well as transmission electron microscope. TGF-ß1 cellular production and macrophage subsets were analyzed by flow cytometry. The relative expressions of targeted proteins and genes were measured by immunofuorescence staining, Western blot, and quantitative polymerase chain reaction. RESULTS: High tidal volume-induced injury and inflammation were resolved at 3 days of post-ventilation (PV3d) to PV10d, with increased elastic fibers, proteoglycans, and collagen content, as well as higher TGF-ß1 levels. M1 macrophages were increased in the acute phase, whereas M2a macrophages began to increase from PV1d to PV3d, as well as increased M2c macrophages from PV3d to PV7d. A single dose of rTGF-ß1 attenuated lung injury and inflammation at end of ventilation with polymorphonuclear leukocyte apoptosis, while nTAb pretreatment induced the abnormal elevation of TGF-ß1 that aggravated lung injury and inflammation due to the significant inhibition of M1 macrophages polarized to M2a, M2b, and M2c macrophages. CONCLUSIONS: Precise secretion of TGF-ß1-mediated macrophage polarization plays a crucial role in the resolution of ventilator-induced inflammatory lung injury.

Use of trimethoprim- sulfamethoxazole for treating Pneumocystis jirovecii pneumonia in a patient with glucose-6-phosphate dehydrogenase deficiency: a case report.

Background: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection caused by the yeast-like fungus P. jirovecii. As recommended by some guidelines, the first-line treatment for this infection is trimethoprim-sulfamethoxazole (TMP-SMX), and the second-line treatment includes drugs such as dapsone, pentamidine, primaquine, Atovaquone, clindamycin, and caspofungin. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked gene disorder in which treatment with oxidizing drugs, such as sulfonamides, dapsone, primaquine, can directly destroy hemoglobin present in red blood cells (RBCs), thereby inducing methemoglobin and hemolysis. Case presentation: Here, we present the case of a lymphoma patient with previous G6PD deficiency who was admitted to ICU for the treatment of severe pneumonia combined with respiratory failure. PJP was detected by the next-generation sequencing of the bronchoalveolar lavage fluid. The patient was initially treated with the antifungal drug caspofungin; however, this treatment showed poor therapeutic effect. Based on the evaluation of G6PD enzyme activity and the patient's previous history of G6PD deficiency, we finally treated the patient with low-dose TMP-SMX combined with caspofungin and provided rigorous medical care to the patient. Following this treatment, the patient's clinical symptoms improved, lung computed tomography showed reduced pulmonary inflammation, and the fungal ß-(1,3)-D-glucan test (G test) showed decreased levels of fungal D-glucan. After 57 days, the TMP-SMX treatment was discontinued. No symptoms related to G6PD deficiency, such as hemolysis, hematuria, and anemia, occurred during the treatment course. Conclusion: This is the first report mentioning the successful treatment of Pneumocystis jirovecii pneumonia with a double-drug regimen with low-dose TMP-SMX and caspofungin in a T-lymphoblastic leukemia/lymphoma patient with previous G6PD deficiency. Enzyme activity detection is the first step for anti-PJP treatment in patients with G6PD deficiency. Although patients with mild enzyme deficiency may not show any adverse reactions, we still recommend the regular monitoring of the levels of RBCs, hemoglobin, and hematocrit before and after the use of sulfonamides or sulfoxides and other oxidizing drugs in patients with G6PD deficiency. Among other things, early and correct diagnosis of Pneumocystis jirovecii pneumonia in hematological malignancies patients is very important. Relevant oncologists should be alert to the risk of Pneumocystis jirovecii pneumonia in these patients.

Effects of dexmedetomidine on early postoperative cognitive function and postoperative inflammatory response: a systematic review and network meta-analysis.

Background: Dexmedetomidine (DEX) has demonstrated potential as an effective agent for enhancing early postoperative cognitive function. However, there is ongoing debate regarding its optimal dosage and impact on early postoperative inflammatory response. This study aimed to assess and prioritize the effects of varying doses of DEX on early postoperative cognitive function and inflammatory response, in order to identify the most effective intervention dosage. Methods: Randomised controlled trials (RCTs) and retrospective cohort studies (RCS) from PubMed, Embase, and Cochrane Library up to January 28, 2024, were included. The Mini-Mental State Examination (MMSE) was utilized to assess the impact of varying doses of DEX on cognitive function during the early postoperative period as the primary outcome, peripheral blood levels of IL-6 and TNF-α were considered as secondary outcomes. Meta-analysis and Bayesian Network Meta-Analysis (NMA) were conducted using R. Funnel plots were generated using Stata 15.0. Results: A total of 29 studies involving 2,807 patients and 25 different doses of DEX were included. DEX was given at a loading dose of 0.3-1.0 µg/kg followed by a maintenance dose of 0.1-0.5 µg/kg/h, or at a uniform intraoperative dose of 0.4-0.7 µg/kg/h. Network meta-analysis revealed most doses of DEX were significantly more effective than normal saline (NS) in improving postoperative MMSE scores (on days 1, 3, and 7) and lowering IL-6 and TNF-α levels. Probability results showed that a 1 µg/kg loading dose followed by a 0.6 µg/kg/h maintenance dose was the best dosing regimen for improving MMSE scores on postoperative days 1 (97.3%), 3 (100%), and 7 (99.9%), as well as for reducing postoperative blood IL-6 levels (1.3%). On the other hand, 0.3 µg/kg followed by 0.2 µg/kg/h was the optimal dosing regimen for reducing postoperative blood TNF-α levels (6.6%). Conclusion: Compared with NS, intraoperative intravenous DEX improved early postoperative cognitive function and postoperative inflammatory response in patients undergoing elective surgery. In particular, a 1 µg/kg loading dose and a 0.6 µg/kg/h maintenance dose resulted in the best improvement in postoperative MMSE scores and blood IL-6 levels, while a 0.3 µg/kg loading dose followed by a 0.2 µg/kg/h maintenance dose is the optimal regimen for lowering postoperative blood TNF-α levels.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=433932, identifier CRD42023433932.

Transforming growth factor-ß1 attenuates inflammation and lung injury with regulating immune function in ventilator-induced lung injury mice.

Ventilator-induced lung injury (VILI) is a lung injury induced or aggravated by mechanical ventilation. Transforming growth factor (TGF)-ß1 is a cytokine that mediates immune function, enabling inflammatory attenuation and tissue repair. Here, we hypothesized that it plays an important role in the attenuation of VILI and inflammation. Ventilation with high tidal volume was performed on C57BL/6 mice to establish a VILI model. After 4 h of ventilation, mice were sacrificed (end of ventilation [EOV]) or extubated for resuscitation at 4 h (post-ventilation 4 h [PV4h]), 8 h (PV8h) and 24 h post-ventilation (PV1d). Recombinant mouse TGF-ß1 (rTGF-ß1) and the neutralization antibody of TGF-ß1 (nTAb) were used in vivo to examine the effect of TGF-ß1 on immune function and inflammatory attenuation in VILI mice. Lung injury was exacerbated at the same trend as the interleukin (IL)-1ß level, peaking at PV1d, whereas IL-6 and tumor necrosis factor (TNF)-α levels gradually reduced. Most active phagosomes, swollen round mitochondria, and cavitating lamellar bodies were observed at PV4h. The CD4+ T cells were significantly increased from PV4h to PV1d, and the CD8a + T cells were higher in the PV4h and PV1d groups; furthermore, the mice in the PV8h group showed highest proportion of CD4+CD8a+ T cells and CD4+/CD8a+ ratio. CD19 + and CD5 + CD19 + B cells in VILI mice began to increase at PV1d. The pulmonary expression of latent and monomer TGF-ß1 increased at PV4h and PV8h. Treatment of rTGF-ß1 only induced high expression of latent and monomer TGF-ß1 at EOV to decrease pulmonary levels of IL-1ß, IL-6, and TNF-α; however, lung injury attenuated from EOV to PV1d. TGF-ß1 induced the delayed elevation of CD4+/CD8a+ T cells ratio and activation of pulmonary CD4+CD8a+ double-positive T cells under certain conditions. Elastic fibers and celluloses, although relatively less proteoglycan, were observed with the overexpression of TGF-ß1 at PV4h and PV8h. In conclusion, TGF-ß1 attenuates the inflammatory response and lung injury of VILI via immune function regulation.

Adenosine A2A Receptor Antagonist Improves Cognitive Impairment by Inhibiting Neuroinflammation and Excitatory Neurotoxicity in Chronic Periodontitis Mice.

The adenosine A2A receptor antagonist SCH58261 has been reported to have anti-inflammatory effects. However, its role in chronic periodontitis (CP)-induced cognitive impairment, which is associated with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS), remains unclear. This study investigated the role of SCH58261 in mice with CP-induced cognitive impairment. C57BL/6J mice were used to develop CP model by injecting 0.5 mg/kg P. gingivalis LPS into the palatal gingival sulcus of maxillary first molars twice a week for four weeks. The mice were divided into control, P. gingivalis LPS (P-LPS), P-LPS + SCH58261, and SCH58261 groups. The passive avoidance test (PAT) and Morris water maze (MWM) were used to assess cognition in mice. Furthermore, CD73/adenosine, neuroinflammation, glutamate transporters, and glutamate were assessed. Compared with the P-LPS group, 0.1 and 0.5 mg/kg SCH58261 increased latency and decreased error times in PAT, but increased platform crossing number in MWM. SCH58261 inhibited microglial activation, and decreased pro-inflammatory cytokines and glutamate levels, but increased GLT-1 and PSD95 expression in the hippocampus. This was the first report of SCH58261 treatment for CP-induced cognitive impairment, which may be related to its anti-inflammatory activities and anti-glutamate excitatory neurotoxicity. This suggests that SCH58261 can be used as a novel agent to treat cognitive impairment.

Arecoline promotes proliferation and migration of human HepG2 cells through activation of the PI3K/AKT/mTOR pathway.

BACKGROUND: Arecoline is a well-known risk factor for oral submucosal fibrosis and cancer. However, the mechanistic correlation between arecoline and hepatocellular cancer remains elusive. Here, we investigated the effect of arecoline on the proliferation and migration of human HepG2 hepatoma cells and its potential oncogenic mechanisms. METHODS: Bioinformatic technologies were used to identify the deferentially expressed miRNAs (DE-miRNAs) and hub target genes of arecoline-induced cancers. These DE-miRNAs, hub genes and pathway were proved in arecoline-treated HepG2 cells. RESULTS: A total of 86 DE-miRNAs and 460 target genes were identified. These target genes are associated with DNA-templated regulation of transcription and other biological processes. Significant molecular functions were protein binding, calcium ion binding, and enrichment in the nucleus and cytoplasm. These genes are involved in the PI3K-AKT pathway. CDK1, CCND1, RAF1, CDKN1B and BTRC were defined as the top 5 hub target genes, and patients with high expression of CDK1 showed poor prognosis. Compared with control group, 2.5 µM arecoline treatment increased the proliferation and migration ability of the HepG2 cells. Treatment with 2.5 µM arecoline increased the levels of miR-21-3p, miR-21-5p and miR-1267, upregulated the expression of PI3K-AKT pathway factors, CDK1, CCND1 but decreased RAF1 expression. CONCLUSION: A low concentration arecoline can induce the proliferation and migration of HepG2 cells, with the potential mechanism of action linked to high levels of exosomal miR-21 and miR-1267, activation of the PI3K-AKT pathway, upregulation of CDK1 and CCND1, and downregulation of RAF1.

Inhibition of TRIM14 protects cerebral ischemia/reperfusion injury through regulating NF-κB/NLRP3 pathway-mediated inflammation and apoptosis.

PURPOSE: Many proteins in tripartite motif (TRIM) family have been reported to play an important role in cerebral ischemia/reperfusion (I/R) injury. This study was designed to investigate the effect of TRIM14 on the cerebral I/R injury in rats. METHODS: The rat model was constructed through inserting thread into the middle cerebral artery. The expression of TRIM14 was measured by qRT-PCR, immunoblotting, and immunofluorescence. The hippocampal sections were stained with 2,3,5-triphenyltetrazolium chloride (TTC) to determine infarct volume and used for measuring the neurologic deficit score and brain water content. The H&E staining was used for immunohistochemical (IHC) staining. The number of apoptotic cells was measured by fluorescence microscopy. The levels of IL-6, IL-1ß, and TNFα were detected by qRT-PCR and ELISA. The swimming speed, latency time, and number of platform crossings were measured by the water maze test. RESULTS: TRIM14 was significantly enhanced in rats with cerebral I/R injury compared to Sham rats, showing its highest level at 24 h after I/R. TRIM14 inhibition reduced ischemic brain injury, suppressed neuron apoptosis, suppressed inflammation, and improved cognitive dysfunction in rats with cerebral I/R injury. TRIM14 inhibition also suppressed the activation of NF-κB/NLRP3 pathway in rats with cerebral I/R injury. CONCLUSION: In conclusion, the expression of TRIM14 was increased in rats with cerebral I/R injury, the protective effect of TRIM14 inhibitor on cerebral I/R injury in rats depends on its anti-apoptotic and anti-inflammatory effect. The underlying mechanism was, at least partially, through regulating NF-κB/NLRP3 pathway.

[Value of creatinine clearance rate estimated based on serum cystatin C in patients with acute kidney injury].

OBJECTIVE: To investigate diagnostic value of creatinine clearance rate (CCr) based on serum cystatin C (SCys C) in acute kidney injury (AKI), and whether it could predict the need for renal replacement therapy (RRT). METHODS: The patients enrolled with the length of intensive care unit (ICU) stay over 3 days were collected from August 2010 to May 2011. According to the diagnosis of AKI during the ICU stay, patients were divided into the AKI group (n=21) and non-AKI group (n=30). After patients were admitted, the level of SCys C and creatinine (SCr) were measured so as to count CCr based on SCys C (SCys C-CCr) or on SCr (SCr-CCr) respectively, meanwhile urine volume and acute physiology and chronic health evaluation II (APACHE II) score were monitored. The value of CCr counted by SCys C and SCr on predict AKI and the correlations between RRT were compared. RESULTS: SCr-CCr and SCys C-CCr in AKI group both were significantly lower than non-AKI group all the way through on admission, and 2 days and 1 day before AKI diagnosed and the day AKI diagnosed. The level of SCys C-CCr on 2 days prior to AKI diagnosed was significantly lower than the day admitted (70.6±8.4 ml×min(-1)×1.73 m(-2) vs. 114.8±15.8 ml×min(-1)×1.73 m(-2), P<0.01), whereas the level of SCr-CCr were not significantly changed (76.4±19.3 ml×min(-1)×1.73 m(-2) vs. 78.7±22.1 ml×min(-1)×1.73 m(-2), P>0.05). Receptor operative curve (ROC) analysis indicated that SCys C-CCr could predict AKI earlier than SCr-CCr, as the area under curve (AUC) of SCys C-CCr and SCr-CCr on 2 days prior to AKI diagnosed were 0.859 and 0.664, respectively, and the sensitivity were 90.5% and 47.6%, the specificity were 76.2% and 81.0%. In AKI group 6 patients were treated with RRT, the AKI patients receiving RRT had significantly higher APACHE II score on admission (29.6±4.5 vs. 17.0±5.6, P<0.05) and less urine volume within 24 hours (740±465 ml vs. 1780±1230 ml, P<0.05) than patients not received RRT, however, SCys C-CCr has no significant difference between the sub-group (50.4±11.2 ml×min(-1)×1.73 m(-2) vs. 53.0±8.4 ml×min(-1)×1.73 m(-2), P>0.05). SCys C-CCr did not predict the need of RRT on the day to diagnose AKI (AUC=0.65). CONCLUSIONS: The sensitivity of SCys C-CCr were high, but its specificity not. The SCys C-CCr may be helpful for excluding diagnose of AKI in high risk patients. However, it could not predict the need for renal replacement therapy on the day AKI diagnosed.