Correlation between vancomycin clearance and cystatin C-based glomerular filtration rate in paediatric patients.

AIMS: Because of limitations with the serum creatinine-based glomerular filtration rate (GFRcr), estimates of the serum cystatin C-based glomerular filtration rate (GFRcys) are getting attention to predict vancomycin clearance (CLvan). We evaluated the correlations between (i) CLvan and GFRcr, and (ii) CLvan and GFRcys in paediatric patients. METHODS: We evaluated a retrospective cohort of patients between 1 and 19 years old admitted to a tertiary hospital between 2017 and 2019. CLvan was estimated using measured vancomycin trough concentrations. We conducted Spearman's correlation analyses between CLvan and 1/creatinine, GFRcr, 1/cystatin C and GFRcys. Subgroup analyses were conducted for the young child, child, adolescent subgroups, intensive care unit patients and low body weight (<10th percentile) patients. RESULTS: We analysed 40 patients. GFRcys correlated with CLvan better than GFRcr did (ρ = 0.731, P < 0.001 vs ρ = 0.504, P = 0.001). In the subgroup analyses, the correlation between GFRcys and CLvan was stronger than that between GFRcr and CLvan (child subgroup ρ = 0.712, P = 0.002 vs ρ = 0.282, P = 0.289; intensive care unit patients ρ = 0.772, P < 0.001 vs ρ = 0.540, P = 0.004; low body weight patients ρ = 0.671, P < 0.001 vs ρ = 0.464, P = 0.022). CONCLUSIONS: Serum cystatin C-based GFR strongly correlates with vancomycin clearance, suggesting the possibility of better prediction models than creatinine-based GFR. Further prospective studies are required for the validation of the prediction model in a large paediatric population.

Nonylphenol increases tumor formation and growth by suppressing gender-independent lymphocyte proliferation and macrophage activation.

Nonylphenol (NP) is a well-known endocrine disruptor that influences sexual and reproductive development. Here, we investigated whether NP affects immune responses that are associated with tumor initiation and progression. When spleen cells were incubated with lipopolysaccharide (LPS) and concanavalin A in the presence of 10-4 M NP, the proliferation of B and T lymphocytes was reduced compared with that in controls, in a gender-independent fashion. While 10-4 M NP also decreased the production of nitric oxide (NO) in LPS-stimulated bone marrow-derived macrophages (BMDMs), no changes in NO production were detected following treatment with 10-5 M NP. LPS-stimulated expression of iNOS, COX2, IL-6 and TNF-α in BMDMs was reduced after 6 or 18 hours of incubation with 10-5 M NP. Furthermore, when mice were pre-exposed to NP for 7 days prior to the injection of B16F10 melanoma cells, the rates of tumor nodule formation and relative tumor growth were higher than those in the control group. In vivo immunosuppressive effect was also clarified by the inhibition of proliferation in B/T lymphocyte and cytokine production in peritoneal macrophages from the mice pretreated with NP for 7 days. Taken together, these data demonstrate that NP could affect the immune responses of lymphocytes and macrophages, leading to the suppression of their tumor-preventing ability. This suggests that individuals at high risk for tumor development should avoid frequent exposure to NP and other endocrine disruptors.

Polarized macrophages treated with nonylphenol differently regulate lipopolysaccharide-induced sepsis.

Nonylphenol (NP) as well-known "endocrine disrupter" influences sexual and reproductive development. Here, we investigated the effect of NP on M1-/M2-type macrophages and their role in lipopolysaccharide (LPS)-induced sepsis. Polarized macrophages of M1- and M2-types were obtained by the treatment with LPS and interleukin-4 (IL-4) to bone marrow-derived macrophages (BMDM), respectively. Coincubation of M1-macrophages with NP decreased COX-2, iNOS, IL-6, and TNF-α expression but no changes were detected in the production of nitric oxide (NO). Survival probability of LPS-induced sepsis mice was enhanced by the injection of NP-treated BMDM as compared to the injection of NP-untreated control BMDM. In the meanwhile, the expression of arginase 1(Arg1), a marker for M2-polarized macrophages was increased by the stimulation with LPS in BMDM. Arg1 expression was also enhanced by the treatment with IL-4 in BMDM, which was reduced by the coincubation with NP. Survival probability of LPS-induced sepsis mice was decreased by the injection of BMDM treated with IL-4 and NP as compared to the injection of IL-4-treated BMDM. It suggests that NP might inhibit macrophage function and the polarization to M2-macrophages. Taken together, data demonstrate that NP could differently affect immune responses of polarized macrophages resulted in the modulation of LPS-induced sepsis. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 2081-2089, 2016.

Efficient Hole Transporting Materials with Two or Four N,N-Di(4-methoxyphenyl)aminophenyl Arms on an Ethene Unit for Perovskite Solar Cells.

Novel steric bulky hole transporting materials (HTMs) with two or four N,N-di(4-methoxyphenyl)aminophenyl units have been synthesized. When the EtheneTTPA was used as a hole transporting material in perovskite solar cell, the power conversion efficiency afforded 12.77 % under AM 1.5 G illumination, which is comparable to the widely used spiro-OMeTAD based solar cell (13.28 %).

Verification of a method using magnetic bead enrichment and nucleic acid extraction to improve the molecular detection of bacterial contamination in blood components.

Bacterial contamination of blood products poses a significant risk in transfusion medicine. Platelets are particularly vulnerable to bacterial growth because they must be stored at room temperature with constant agitation for >5 days. The limitations of bacterial detection using conventional methods, such as blood cultures and lateral flow assays, include the long detection times, low sensitivity, and the requirement for substantial volumes of blood components. To address these limitations, we assessed the performance of a bacterial enrichment technique using antibiotic-conjugated magnetic nanobeads (AcMNBs) and real-time PCR for the detection of bacterial contamination in plasma. AcMNBs successfully captured >80% of four bacterial strains, including Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Klebsiella pneumoniae, in both plasma and phosphate-buffered saline. After 24-h incubation with bacterial enrichment, S. aureus and B. cereus were each detected at 101 CFU/mL in all trials (5/5), E. coli at 101 CFU/mL in 1/5 trials, and K. pneumoniae at 10² CFU/mL in 4/5 trials. Additionally, without incubation, the improvement was also achieved in samples with bacterial enrichment, S. aureus at 10² CFU/mL and B. cereus at 101 CFU/mL in 1/5 trials each, E. coli at 10³ CFU/mL in 3/5 trials, and K. pneumoniae at 10¹ CFU/mL in 2/5 trials. Overall, the findings from this study strongly support the superiority of bacterial enrichment in detecting low-level bacterial contamination in plasma when employing AcMNBs and PCR.IMPORTANCEThe study presents a breakthrough approach to detect bacterial contamination in plasma, a critical concern in transfusion medicine. Traditional methods, such as blood cultures and lateral flow assays, are hampered by slow detection times, low sensitivity, and the need for large blood sample volumes. Our research introduces a novel technique using antibiotic-conjugated magnetic nanobeads combined with real-time PCR, enhancing the detection of bacteria in blood products, especially platelets. This method has shown exceptional efficiency in identifying even low levels of four different species of bacteria in plasma. The ability to detect bacterial contamination rapidly and accurately is vital for ensuring the safety of blood transfusions and can significantly reduce the risk of infections transmitted through blood products. This advancement is a pivotal step in improving patient outcomes and elevating the standards of care in transfusion medicine.

Evaluation of adverse drug reactions in medical intensive care units.

PURPOSE: Patterns of adverse drug reactions (ADRs) in the medical intensive care unit (MICU) were analysed, and signals for detecting ADRs were developed from the analysis. METHOD: A retrospective study was conducted in MICU wards at a tertiary care teaching hospital in Seoul, Korea. The areas included one general MICU and one cancer centre MICU. Two pharmacists evaluated ADRs in terms of length of stay, causality, severity, preventability, types, related organs, and incidence. Differences in ADR perception rates between physicians and pharmacists were also evaluated. ADR cases detected through the evaluation were reviewed to develop specific alerting signals for ICU ADRs. RESULTS: The study group included 346 patients admitted to the ICU over 4 months. The overall incidence of ADRs was 32%. ICU length of stay is closely related to ADRs (p = 0.014). Most ADR cases were mild, temporary, and harmful to the patient. Twenty percent of ADRs were preventable, and 74% were type A. Of the ADRs, 70% were noted by physicians; 80% required intervention. The most commonly implicated drug was amphotericin B, and the clinical presentation was a haematologic reaction. Data on the time required for pharmacists to identify ADRs indicated that they were not slower than physicians. Six signals for early detection of the ADRs were developed. CONCLUSIONS: The overall ADR incidence in the MICU was about one-third, and the length of stay of the ADR group was longer than that of those without this experience. Automated signal generation was developed. It seemed to be a valuable tool for faster and more efficient patient management, and possibly prevention of ADRs. A future study should scientifically evaluate the clinical relevance of this tool.

Long-term changes in the concentrations of nutrients in the marginal seas (Yellow Sea, East China Sea, and East/Japan Sea) neighboring the Korean Peninsula.

We examined the changes in the concentrations of dissolved inorganic nitrogen (DIN) and phosphorus (DIP) in the surface waters of the Yellow Sea (YS), the southern sea (SS) of Korea, and the East/Japan Sea (ES) from 1995 to 2021. These marginal seas neighboring the Korean Peninsula maintained nutrient concentrations approximately an order of magnitude higher than those in the Kuroshio waters, indicating extraordinarily large terrestrial source inputs. Generally, the DIN concentration in the YS increased gradually due to the accumulation of terrestrial inputs, while the nutrient concentrations in the ES declined gradually mainly due to enhanced water stratification. The SS showed the maximum DIN concentrations around 2005, associated with freshwater influence. In Korean coastal waters within ~10 km from the coastline, nutrient concentrations declined sharply during this period due to decreased terrestrial nutrient inputs. The rapid changes in the nutrient levels in these seas may significantly alter biological production.

Physical and functional interactions of Caenorhabditis elegans WRN-1 helicase with RPA-1.

The Caenorhabditis elegans Werner syndrome protein, WRN-1, a member of the RecQ helicase family, has a 3'-5' DNA helicase activity. Worms with defective wrn-1 exhibit premature aging phenotypes and an increased level of genome instability. In response to DNA damage, WRN-1 participates in the initial stages of checkpoint activation in concert with C. elegans replication protein A (RPA-1). WRN-1 helicase is stimulated by RPA-1 on long DNA duplex substrates. However, the mechanism by which RPA-1 stimulates DNA unwinding and the function of the WRN-1-RPA-1 interaction are not clearly understood. We have found that WRN-1 physically interacts with two RPA-1 subunits, CeRPA73 and CeRPA32; however, full-length WRN-1 helicase activity is stimulated by only the CeRPA73 subunit, while the WRN-1(162-1056) fragment that harbors the helicase activity requires both the CeRPA73 and CeRPA32 subunits for the stimulation. We also found that the CeRPA73(1-464) fragment can stimulate WRN-1 helicase activity and that residues 335-464 of CeRPA73 are important for physical interaction with WRN-1. Because CeRPA73 and the CeRPA73(1-464) fragment are able to bind single-stranded DNA (ssDNA), the stimulation of WRN-1 helicase by RPA-1 is most likely due to the ssDNA binding activity of CeRPA73 and the direct interaction of WRN-1 and CeRPA73.

Bioconversion of Mixed Alkanes to Polyhydroxyalkanoate by Pseudomonas resinovornas: Upcycling of Pyrolysis Oil from Waste-Plastic.

Polyhydroxyalkanoate (PHA) is a biodegradable plastic that can be used to replace petroleum-based plastic. In addition, as a medium-chain-length PHA (mcl-PHA), it can be used to provide elastomeric properties in specific applications. Because of these characteristics, recently, there has been much research on mcl-PHA production using inexpensive biomass materials as substrates. In this study, mcl-PHA producers were screened using alkanes (n-octane, n-decane, and n-dodecane) as sources of carbon. The amount of PHA produced by Pseudomonas resinovorans using sole n-octane, n-decane, or n-dodecane was 0.48 g/L, 0.27 g/L, or 0.07 g/L, respectively, while that produced using mixed alkane was 0.74 g/L. As a larger amount of PHA was produced using mixed alkane compared with sole alkane, a statistical mixture analysis was used to determine the optimal ratio of alkanes in the mixture. The optimal ratio predicted by the analysis was a medium with 9.15% n-octane, 6.44% n-decane, and 4.29% n-dodecane. In addition, through several concentration-specific experiments, the optimum concentrations of nitrogen and phosphorus for cell growth and maximum PHA production were determined as 0.05% and 1.0%, respectively. Finally, under the determined optimal conditions, 2.1 g/L of mcl-PHA and 60% PHA content were obtained using P. resinovorans in a 7 L fermenter.

Deep Learning Model Based on 3D Optical Coherence Tomography Images for the Automated Detection of Pathologic Myopia.

Pathologic myopia causes vision impairment and blindness, and therefore, necessitates a prompt diagnosis. However, there is no standardized definition of pathologic myopia, and its interpretation by 3D optical coherence tomography images is subjective, requiring considerable time and money. Therefore, there is a need for a diagnostic tool that can automatically and quickly diagnose pathologic myopia in patients. This study aimed to develop an algorithm that uses 3D optical coherence tomography volumetric images (C-scan) to automatically diagnose patients with pathologic myopia. The study was conducted using 367 eyes of patients who underwent optical coherence tomography tests at the Ophthalmology Department of Incheon St. Mary's Hospital and Seoul St. Mary's Hospital from January 2012 to May 2020. To automatically diagnose pathologic myopia, a deep learning model was developed using 3D optical coherence tomography images. The model was developed using transfer learning based on four pre-trained convolutional neural networks (ResNet18, ResNext50, EfficientNetB0, EfficientNetB4). Grad-CAM was used to visualize features affecting the detection of pathologic myopia. The performance of each model was evaluated and compared based on accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). The model based on EfficientNetB4 showed the best performance (95% accuracy, 93% sensitivity, 96% specificity, and 98% AUROC) in identifying pathologic myopia.

Clinical phenotypes of delirium in patients admitted to the cardiac intensive care unit.

BACKGROUND: Limited data are available on clinical phenotype for delirium that occurs frequently among patients admitted to the cardiac intensive care unit (CICU). The objective of this study was to investigate the clinical pictures of delirium, and their association with clinical outcomes in CICU patients. METHODS: A total of 4,261 patients who were admitted to the CICU between September 1 2012 to December 31 2018 were retrospectively registered. Patients were excluded if they were admitted to the CICU for less than 24 hours or had missed data. Ultimately, 2,783 patients were included in the analysis. A day of delirium was defined as any day during which at least one CAM-ICU assessment was positive. The clinical risk factors of delirium were classified by the delirium phenotype, as follows; hypoxic, septic, sedative-associated, and metabolic delirium. RESULTS: The incidence of delirium was 24.4% at the index hospitalization in all CICU patients, and 22.6% within 7 days after CICU admission. The most common delirium phenotype was septic delirium (17.2%), followed by hypoxic delirium (16.8%). Multiple phenotypes were observed during most delirium days. Delirium most frequently occurred in patients with heart failure. Of all patients affected by delirium within 7 days, both ICU and hospital mortality significantly increased according to the combined number of delirium phenotypes. CONCLUSIONS: Delirium occurred in a quarter of patients admitted to the modern CICU and was associated with increased in-hospital mortality. Therefore, more efforts are needed to reduce the clinical risk factors of delirium, and to prevent it in order to improve clinical outcomes in the CICU.

Spleen tyrosine kinase regulates crosstalk of hypoxia-inducible factor-1α and nuclear factor (erythroid-derived2)-like 2 for B cell survival.

B cells play a major role in regulating disease incidence through various factors, including spleen tyrosine kinase (Syk), which transmits signals to all hematopoietic lineage cells. Hypoxia-inducible factor (HIF)-1α accumulates under hypoxic conditions, which is also oxidative stress to induce nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responsible for gene expression of antioxidant enzymes. In the present study, we investigated whether B cells are regulated by crosstalk of HIF-1α and Nrf2 via reactive oxygen species (ROS)-mediated Syk activation. When B cells were incubated under hypoxic conditions, Syk phosphorylation, HIF-1α, and Nrf2 levels were increased. Hypoxia-inducible results were consistent with CoCl2 treatment, which mimics hypoxic conditions. Cell viability was reduced by the Syk inhibitor BAY 61-3606. Increased Nrf2 levels due to hypoxia or CoCl2 were inhibited by treatment with a HIF inhibitor. Hypoxia- or CoCl2-induced ROS increased HIF-1α and Nrf2 levels, which were attenuated by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. HIF-1α levels were reduced in doxycycline-treated shNrf2 cells. Clobetasol propionate, a Nrf2 inhibitor, also inhibited HIF-1α levels induced by hypoxia or CoCl2. ROS-mediated Syk phosphorylation at tyrosine 525/526 was confirmed by treatment with H2O2, hypoxia, and CoCl2, and attenuated with NAC treatment. Inhibition of Syk phosphorylation by BAY 61-3606 is consistent with a decrease in protein HIF-1α and Nrf2 levels. Taken together, HIF-1α levels might control Nrf2 levels and vice versa, and could be associated with Syk phosphorylation in B cells. The results indicate that B cells could be regulated by crosstalk of HIF-1α and Nrf2 through ROS-mediated Syk activation.

BAFF attenuates oxidative stress-induced cell death by the regulation of mitochondria membrane potential via Syk activation in WiL2-NS B lymphoblasts.

Cell survival is facilitated by the maintenance of mitochondrial membrane potential (MMP). B cell activating factor (BAFF) plays a role in survival, differentiation, and maturation of B cells. In the present study, we examined whether BAFF could attenuate oxidative stress-induced B cell death by the regulation of MMP collapse via spleen tyrosine kinase (Syk) activation using WiL2-NS human B lymphoblast cells. BAFF binds to receptors on WiL2-NS cells. When the cells were incubated in serum-deprived conditions with 1% fetal bovine serum (FBS), BAFF reduced the percentage of dead cells as determined through trypan blue staining and caspase 3 activity. BAFF also inhibited MMP collapse with 1% FBS, as indicated by a decrease in the number of cells with high-red fluorescence of MitoProbe™ JC-1 reagent or a decrease in the percentage of DiOC6-stained cells. Reactive oxygen species (ROS) production was reduced by incubation with BAFF in the presence of 10% or 1% FBS. BAFF inhibited MMP collapse, cell growth retardation, dead cell formation, and caspase 3 activation caused by treatment with H2O2. Syk phosphorylation on tyrosine (Y) 525/526 was increased in cells incubated with 1% FBS in the presence of BAFF than cells incubated with 1% FBS or BAFF alone. BAY61-3606, a Syk inhibitor reduced the effect of BAFF on MMP collapse, caspase 3 activation, cell growth retardation, and dead cell formation. Together, these data demonstrate that BAFF might attenuate oxidative stress-induced B cell death and growth retardation by the maintenance of MMP through Syk activation by Y525/526 phosphorylation. Therefore, BAFF and Syk might be therapeutic targets in the pathogenesis of B cell-associated diseases such as autoimmune disease.

Cs desorption behavior during hydrothermal treatment of illite with oxalic acid.

The desorption of radioactive cesium (Cs) in soil is influenced by the clay mineral type, adsorption site, and concentration of Cs. In this study, experiments to detect desorption of non-radioactive and radioactive Cs from illite using oxalic acid were performed for 2 days at 70 °C in hydrothermal conditions. The results showed that the 133Cs removal efficiency by oxalic acid and inorganic acid treatment was similar at high concentration (22.86 mmol/kg) of non-radioactive 133Cs. In the radioactive 137Cs experiment, the removal efficiency by oxalic acid was higher than that by inorganic acid at low concentration (0.79 × 10-6 mmol/kg) of radioactive 137Cs. Based on the illite hypothetical frayed edge site (FES) concentration of 0.612 mmol/kg, the results suggested that 137Cs was preferentially adsorbed to FES on illite. The 137Cs at low concentration was difficult to remove because it was irreversible adsorption to FES, while the non-radioactive Cs at high concentration was mainly adsorbed to planar sites, and so was easy to desorb by ion exchange. Based on the results of NMR, FTIR, and XPS analyses, we concluded that the higher efficiency of 137Cs removal at low concentration by oxalic acid treatment than by treatment with inorganic acid was because of chelation effects associated with the complexation of oxalic acid (ligands) and metal ions in irreversible site (FES).

Drain placement in thyroidectomy is associated with longer hospital stay without preventing hematoma.

OBJECTIVE: To analyze the effect of drain placement on postoperative hematoma formation and other associated outcomes post-thyroid surgery in a large national cohort. METHODS: This was a retrospective study that analyzed data from the 2016-2017 National Surgical Quality Improvement Program (NSQIP) public use files. Baseline characteristics and perioperative outcomes were compared between drain and no drain cohorts. RESULTS: A total of 11,626 patients were included; 3281 had a drain placed intraoperatively and 8345 did not. Otolaryngologists were 6.98 times more likely to place a drain after thyroidectomy than general surgeons (P < .001), and patients undergoing subtotal or total thyroidectomy were 2.17 times more likely to have a drain placed than if undergoing partial thyroidectomy (P < .001). Drain placement did not reduce hematoma formation on both univariate and multivariate analyses (adjusted OR = 0.93, P = .696). A slightly larger proportion of patients underwent unplanned intubation postoperatively among those who had a drain placed (0.76% vs. 0.29%, P < .001). Patients who received a drain were on average 4.63 times as likely to remain in the hospital for 2 or more days compared to those who did not receive a drain. CONCLUSION: Drain placement did not significantly affect postoperative hematoma formation following thyroidectomy. Drain placement should not be routinely employed in these patients. However, surgeon judgement and intraoperative considerations should be taken into account, as to when to place a drain. LEVEL OF EVIDENCE: N/A Laryngoscope, 130:1349-1356, 2020.

Evaluation of optimal culture conditions for recombinant ghost bacteria vaccine production with the antigen of Streptococcus iniae GAPDH.

For the production of ghost bacteria vaccine to prevent the streptococcal disease in aquaculture fish species, a double cassettes vector was constructed and cloned in Escherichia coli DH5alpha. Ghost bacteria vaccine production from Escherichia coli DH5alpha/pHCE-InaN-GAPDH-Ghost 37 SDM (SIG) was maximized at a glucose concentration of 1 g/l, agitation of 300 rpm, and aeration of 1 vvm. The maximal efficiency of ghost bacteria formation was obtained at the mid-exponential phase (OD600=2.0) with the concentration of 0.77 g/l for SIG. The molecular mass of GAPDH was detected at 67 kDa with the insoluble fraction, by SDS-PAGE and Western blot. The protective efficacy of ghost bacteria vaccine was evaluated by challenge test using olive flounder. The cumulative mortalities of the positive control, formalin-killed cell (FKC) vaccine, and SIG vaccine immunized groups were 91% , 74% , and 57% , respectively. These results suggest that SIG vaccine showed efficacy as a vaccine and had a higher potential to induce protective antibodies than did FKC vaccine.

Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.

OBJECTIVES: Prior studies suggest that oxaliplatin is unique among platinum chemotherapy drugs in its ability to enhance anti-tumor immunity, but the immune mechanisms of different platinum chemotherapy drugs have not been previously compared in preclinical models of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Human HNSCC cell lines were treated with cisplatin or oxaliplatin, then assessed for markers associated with immunogenic cell death (ICD) and antigen processing. A syngeneic mouse model of oral cancer was then used to compare the effects of cisplatin vs. oxaliplatin, alone or in combination with anti-PD-1 immunotherapy, on tumor growth and survival. A subset of spleens and tumors were analyzed for ICD markers and immune cell infiltrates by flow cytometry. RESULTS: Cisplatin and oxaliplatin both increased cell surface levels of calreticulin, HSP70, MHC class I and PD-L1 in multiple cell lines. Inoculation of immunocompetent mice with cells killed in vitro by either drug resulted in failure of subsequently-injected live tumor cells to establish and grow in a small proportion of animals. Systemic cisplatin and oxaliplatin induced similar tumor growth delay when combined with anti-PD-1 therapy. CONCLUSIONS: Treatment of HNSCC cells with platinum chemotherapy appears to induce some features of anti-tumor immunity, which may be enhanced by anti-PD-1 therapy. Cisplatin, the standard drug for HNSCC, appears to affect anti-tumor immunity in a similar fashion to oxaliplatin in these preclinical models.

Effects of continuous ketamine infusion on hemodynamics and mortality in critically ill children.

We investigated the hemodynamic and mortality effects of continuous ketamine infusion in critically ill pediatric patients. We conducted a retrospective cohort study in a tertiary pediatric intensive care unit (PICU). Patients who used continuous sedative from 2015 to 2017 for 24 hours or more were included. We compared blood pressure, heart and respiratory rates, vasogenic medications, and sedation and pain scores for 12 hours before and after initiation of continuous ketamine. The mortality rates for continuous ketamine and Non-ketamine groups were compared by multivariate logistic regression. A total of 240 patients used continuous sedation, and 82 used continuous ketamine. The median infusion rate of ketamine was 8.1 mcg/kg/min, and the median duration was 6 days. Heart rates (138 vs. 135 beat/minute, P = .033) and respiratory rates (31 vs. 25 respiration/minute, P = .001) decreased, but blood pressure (99.9 vs. 101.1 mm Hg, P = .124) and vasogenic medications did not change after ketamine infusion. Continuous ketamine was not a significant risk factor for mortality (hazard ratio 1.352, confidence interval 0.458-3.996). Continous ketamine could be used in PICU without hemodynamic instability. Further studies in randomized controlled design about the effects of continuous ketamine infusion on hemodynamic changes, sedation, and mortality are required.

Spleen tyrosine kinase-dependent Nrf2 activation regulates oxidative stress-induced cell death in WiL2-NS human B lymphoblasts.

Autoimmune rheumatic lesions are often characterised by the immune cell recruitment including B lymphocytes and the presence of reactive oxygen species (ROS), which increase antioxidant gene transcription via nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Spleen tyrosine kinase (Syk) has a major role in the signal transmission of all haematopoietic lineage cells including B/T cells, mast cells, and macrophages. In this study, we investigated whether B cell survival is regulated by Nrf2 via ROS-mediated Syk activation in WiL2-NS human B lymphoblast cells. When WiL2-NS cells were incubated with 1% foetal bovine serum (FBS), the survival rate and mitochondrial membrane potential (MMP) were reduced. In addition, 1% FBS increased caspase 3 activity, cytochrome C release, nuclear localisation of Nrf2, and ROS production. N-acetylcysteine attenuated ROS production and nuclear translocation of Nrf2. It also inhibited cell death, caspase 3 activation, MMP collapse, and cytochrome C release. Results from the 1% FBS treatment were consistent with those of H2O2 treatment. Syk phosphorylation at tyrosine 525/526 was increased by incubation with 1% FBS or treatment with 100 µM H2O2. Nuclear translocation of Nrf2 by H2O2 was inhibited by treatment with BAY61-3606, a Syk inhibitor. BAY61-3606 also promoted MMP collapse, cytochrome C release, caspase 3 activation, and cell death. Taken together, these results implicate that Syk controls oxidative stress-induced human B cell death via nuclear translocation of Nrf2 and MMP collapse. These results suggest that Syk is a novel regulator of Nrf2 activation.

Di-(2-ethylhexyl) phthalate enhances melanoma tumor growth via differential effect on M1-and M2-polarized macrophages in mouse model.

Phthalates are widely used as plasticizers that influence sexual and reproductive development. Here, we investigated whether di-(2-ethylhexyl) phthalate (DEHP) affects macrophage polarization that are associated with tumor initiation and progression. No changes were observed in LPS- or ConA-stimulated in vitro spleen B or T cell proliferation for 48 h, respectively. In contrast, macrophage functions were inhibited in response to DEHP for 12 h as judged by LPS-induced H2O2 and NO production and zymosan A-mediated phagocytosis. When six weeks old male mice were pre-exposed to 4.0 mg/kg DEHP for 21 days before the injection of B16F10 melanoma cells and post-exposed to 4.0 mg/kg DEHP for 7 days, tumor nodule formation and the changes in tumor volume were higher than those in control group. Furthermore, when male mice were intraperitoneally pretreated with DEHP for 3 or 4 weeks and peritoneal exudate cells (PECs) or bone marrow-derived macrophages (BMDMs) were incubated with lipopolysaccharide (LPS), the expression of COX-2, TNF-α, and IL-6 was reduced in DEHP-pretreated cells as compared with that in LPS-stimulated control cells. While the production of nitric oxide (NO) for 18 h was reduced by LPS-stimulated PECs and M1-type BMDMs, IL-4 expression was enhanced in LPS-stimulated BMDMs. When BMDMs were incubated with IL-4 for 30 h, arginase 1 for M2-type macrophages was increased in transcriptional and translational level. Data implicate that macrophages were differentially polarized by DEHP treatment, which reduced M1-polarzation but enhanced M2-polarization. Taken together, these data demonstrate that DEHP could affect in vivo immune responses of macrophages, leading to the suppression of their tumor-preventing ability. This suggests that individuals at high risk for tumor incidence should avoid long-term exposure to various kind of phthalate including DEHP.