Management of Immunosuppressive Therapy in Kidney Transplant Recipients with Sepsis: A Multicenter Retrospective Study.

BACKGROUND: Up to 6% of kidney transplant recipients (KTRs) experience life-threatening complications requiring intensive care unit (ICU) admission, and one of the most common medical complications requiring ICU admission is infection. This study aimed to evaluate the effect of immunosuppressive therapy (IST) modification on prognosis of KTRs with sepsis. METHODS: We conducted a multicenter retrospective study in 4 university-affiliated hospitals to evaluate the effect of adjusting the IST in KTRs with sepsis. Only patients who either maintained IST after ICU admission or those who underwent immediate (within 24 h of ICU admission) reduction or withdrawal of IST following ICU admission were included in this study. "Any reduction" was defined as a dosage reduction of any IST or discontinuation of at least 1 IST. "Complete withdrawal of IST" was defined as concomitant discontinuation of all ISTs, except steroids. RESULTS: During the study period, 1596 of the KTRs were admitted to the ICU, and 112 episodes of sepsis or septic shock were identified. The overall in-hospital mortality rate was 35.7%. In-hospital mortality was associated with higher sequential organ failure assessment score, simplified acute physiology score 3, non-identical human leukocyte antigen relation, presence of septic shock, and complete withdrawal of IST. After adjusting for potential confounding factors, complete withdrawal of IST remained significantly associated with in-hospital mortality (adjusted coefficient, 1.029; 95% confidence interval, 0.024-2.035) and graft failure (adjusted coefficient, 2.001; 95% confidence interval, 0.961-3.058). CONCLUSIONS: Complete IST withdrawal was common and associated with worse outcomes in critically ill KTRs with sepsis.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis.

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.

Cellular signaling crosstalk between Wnt signaling and gap junctions inbenzo[a]pyrene toxicity.

Gap junctional intercellular communication (GJIC) is considered a key biological mechanism to maintain homeostasis in cell differentiation and growth. In addition, as another major signaling pathway associated with cell proliferation and differentiation, Wnt/ß-catenin signaling appears to trigger several cellular responses against injury. The purpose of the present study was to investigate the effects of a known toxic agent, benzo[a]pyrene (BaP), on the regulation and interaction between GJIC and Wnt/ß-catenin signaling. BaP treatment resulted in GJIC inhibition and decreases the major GJIC protein connexin 43 (Cx43) in WB-F344 rat liver epithelial cells. We also found BaP-mediated downregulation of Wnt/ß-catenin signaling related to the PI3K-Akt pathway. To identify the relationship between GJIC and Wnt/ß-catenin signaling, we treated WB-F344 cells with the Wnt agonist CHIR99021 and found that it inhibited GJIC while causing a significant reduction in Cx43 expression at both the mRNA and protein levels, through the repression of promoter activity. This Wnt agonist-mediated GJIC inhibition was confirmed using a small interfering RNA directed against the Wnt antagonist Dact2, indicating that Wnt/ß-catenin signaling negatively regulates GJIC. Despite the inverse correlation between Wnt/ß-catenin signaling and Cx43 promoter activation as indicated by downregulation of ß-catenin nuclear translocation and upregulation of Cx43 promoter activation involving HNF3ß, BaP treatment decreased the Cx43 protein expression, which was associated with protein degradation, possibly through protein kinase C activation. In conclusion, our results revealed the mechanism of BaP-induced inhibition of GJIC and Wnt/ß-catenin signaling. More importantly, linking Wnt/ß-catenin signaling to Cx protein expression will have profound implications in understanding the relationships among different major signaling pathways associated with cell proliferation and differentiation in toxicity.

Distinguishing nontuberculous mycobacterial lung disease and Mycobacterium tuberculosis lung disease on X-ray images using deep transfer learning.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTM-LD) and Mycobacterium tuberculosis lung disease (MTB-LD) have similar clinical characteristics. Therefore, NTM-LD is sometimes incorrectly diagnosed with MTB-LD and treated incorrectly. To solve these difficulties, we aimed to distinguish the two diseases in chest X-ray images using deep learning technology, which has been used in various fields recently. METHODS: We retrospectively collected chest X-ray images from 3314 patients infected with Mycobacterium tuberculosis (MTB) or nontuberculosis mycobacterium (NTM). After selecting the data according to the diagnostic criteria, various experiments were conducted to create the optimal deep learning model. A performance comparison was performed with the radiologist. Additionally, the model performance was verified using newly collected MTB-LD and NTM-LD patient data. RESULTS: Among the implemented deep learning models, the ensemble model combining EfficientNet B4 and ResNet 50 performed the best in the test data. Also, the ensemble model outperformed the radiologist on all evaluation metrics. In addition, the accuracy of the ensemble model was 0.85 for MTB-LD and 0.78 for NTM-LD on an additional validation dataset consisting of newly collected patients. CONCLUSIONS: In previous studies, it was known that it was difficult to distinguish between MTB-LD and NTM-LD in chest X-ray images, but we have successfully distinguished the two diseases using deep learning methods. This study has the potential to aid clinical decisions if the two diseases need to be differentiated.

The effect and associated mechanism of action of phosphodiesterase 4 (PDE4) inhibitor on CD4+ lymphocyte proliferation.

PDE4 inhibitors are involved in anti-inflammatory and immunomodulatory responses. Recently, they have been getting attention as a new class of drugs treating inflammatory airway diseases. The T lymphocyte is a major cell type present in the inflammatory infiltrate in the airway wall in patients with chronic obstructive pulmonary disease (COPD), and a previous study found that treatment with a PDE4 inhibitor significantly suppressed T cell proliferation. However, the mechanism of action of PDE4 inhibitors has not been elucidated. The present study aimed to investigate major signal transduction pathways of T lymphocyte and identify the phase, during which PDE4 inhibitors affect T cell proliferation. Isolated splenic CD4+ T cells were grown under stimulation with an anti-CD3/CD28 antibody, and/or treated with roflumilast-n-oxide (RNO). A western blot assay was performed using major antibodies including anti-p-38, anti-p-PI3K, anti-p-JNK, anti-p-ERK 1/2, anti-NFAT1 (NFATc2), and anti-NF-kB antibodies. Additional experiments conducted on the pathway showed significant change following RNO treatment, thus providing further evidence for signal transduction pathway concerning PDE4 inhibitors. T cell proliferation was suppressed by RNO treatment. In the pathways involved in T cell proliferation, only expression of anti-NFAT1 antibody was suppressed by RNO treatment. In additional experiments on the NFAT pathway, the very first phase (TCR signalling) remained unchanged on treatment with RNO, but RNO treatment increased IP3R expression and suppressed calcineurin activity. Calcineurin activity, reduced by RNO, increased on treatment with an IP3 receptor agonist. PED4 inhibitor, roflumilast is speculated to suppress T cell proliferation by interfering with IP3-IP3R binding to inhibit calcium emission, blocking pathway activation from this phase onward, eventually decreasing the level of a growth factor for T cell proliferation, IL-2.

Commercial video games and cognitive functions: video game genres and modulating factors of cognitive enhancement.

BACKGROUND: Unlike the emphasis on negative results of video games such as the impulsive engagement in video games, cognitive training studies in individuals with cognitive deficits showed that characteristics of video game elements were helpful to train cognitive functions. Thus, this study aimed to have a more balanced view toward the video game playing by reviewing genres of commercial video games and the association of video games with cognitive functions and modulating factors. Literatures were searched with search terms (e.g. genres of video games, cognitive training) on database and Google scholar. RESULTS: video games, of which purpose is players' entertainment, were found to be positively associated with cognitive functions (e.g. attention, problem solving skills) despite some discrepancy between studies. However, the enhancement of cognitive functions through video gaming was limited to the task or performance requiring the same cognitive functions. Moreover, as several factors (e.g. age, gender) were identified to modulate cognitive enhancement, the individual difference in the association between video game playing and cognitive function was found. CONCLUSION: Commercial video games are suggested to have the potential for cognitive function enhancement. As understanding the association between video gaming and cognitive function in a more balanced view is essential to evaluate the potential outcomes of commercial video games that more people reported to engage, this review contributes to provide more objective evidence for commercial video gaming.

Protective effects of diphenyleneiodonium, an NADPH oxidase inhibitor, on lipopolysaccharide-induced acute lung injury.

NADPH oxidase (NOX) plays an important role in inflammatory response by producing reactive oxygen species (ROS). The inhibition of NOX has been shown to induce anti-inflammatory effects in a few experimental models. The aim of this study was to investigate the effects of diphenyleneiodonium (DPI), a NOX inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a rat model. Sprague-Dawley rats were intraperitoneally administered by DPI (5 mg/kg) 30 minutes after intratracheal instillation of LPS (3 mg/kg). After 6 hours, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The NOX activity in lung tissue was significantly increased in LPS-treated rats. It was significantly attenuated by DPI. DPI-treated rats showed significant reduction in the intracellular ROS, the number of inflammatory cells, and cytokines (TNF-α and IL-6) in BALF compared with LPS-treated rats. In lung tissue, DPI-treated rats showed significantly decreased malondialdehyde content and increased activity of glutathione peroxidase and superoxide dismutase compared with LPS-treated rats. Lung injury score, myeloperoxidase activity, and inducible nitric oxide synthase expression were significantly decreased in DPI-treated rats compared with LPS-treated animals. Western blotting analysis demonstrated that DPI significantly suppressed LPS-induced activation of NF-κB and ERK1/2 and SAPK/JNK in MAPK pathway. Our results suggest that DPI may have protective effects on LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects which may be due to inactivation of the NF-κB, ERK1/2, and SAPK/JNK pathway. These results suggest the therapeutic potential of DPI as an anti-inflammatory agent in ALI.

Early Prediction of Hypertensive Disorders of Pregnancy Using Cell-Free Fetal DNA, Cell-Free Total DNA, and Biochemical Markers.

OBJECTIVE: To evaluate the predictive value of separate and combined tests using cell-free fetal DNA (cffDNA), cell-free total DNA (cfDNA), and biochemical markers for the early detection of pregnancies with hypertensive disorders. METHODS: A nested case-control study was conducted with 135 singleton pregnancies including 17 gestational hypertension cases, 34 preeclampsia (PE) cases, and 84 controls. We performed real-time quantitative PCR to measure levels of DSCR3 and RASSF1A as cffDNA markers and HYP2 as a cfDNA marker in the first and early second trimesters. Levels of pregnancy-associated plasma protein A (PAPP-A), α-fetoprotein, ß-human chorionic gonadotropin, unconjugated estriol, and inhibin A were also determined. RESULTS: Compared with controls, the median levels and multiples of the median (MoM) values of HYP2 were significantly higher in the PE and hypertensive disorders of pregnancy (HDP) groups at 6-14 and 15-23 weeks. Frist-trimester PAPP-A MoM was significantly lower in PE and HDP than in controls. For PE and HDP, the best model included the first-trimester DSCR3, HYP2, and PAPP-A MoM values achieving detection rates of 67 and 58% at a fixed 10% false-positive rate, respectively [area under the receiver operating characteristic curve 0.832 (95% CI 0.689-0.928) for PE; 0.751 (0.607-0.863) for HDP]. DISCUSSION: The study demonstrates the potential utility of combined first-trimester cffDNA, cfDNA, and PAPP-A for the early prediction of PE.

The role of PET/CT in diagnosing generalized lymphadenopathy in asymptomatic secondary syphilis.

OBJECTIVE: Syphilis is a well-known sexually transmitted disease, and has multiple stages and various symptoms. However, it is difficult to diagnose syphilis in patients who may have no clinical symptoms. Because of these reasons, there have been several case reports on misdiagnosis of syphilis. Generalized lymphadenopathy could be an indication of various diseases including malignancies or infections. CONCLUSION: We report a case of a secondary syphilis in a patient with generalized lymphadenopathy detected by fluorine-18-fluorodeoxy glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) images without any clinical symptom. Clinical examination found an ulcer on his penis and serologic tests set the diagnosis of an early stage of secondary syphilis.

Predictive Markers of Tubo-Ovarian Abscess in Pelvic Inflammatory Disease.

BACKGROUND/AIMS: The purpose of this study was to identify predictive markers for tubo-ovarian abscess (TOA) through a comparison of clinical and laboratory data in patients diagnosed with pelvic inflammatory disease (PID). METHODS: We reviewed the medical charts of 499 females who were admitted to hospital with clinical, surgical, imaging-based diagnoses of PID between 2001 and 2011. The patients were divided into the following two groups: (1) PID with TOA and (2) PID without TOA. RESULTS: The TOA and non-TOA groups were comprised of 69 and 430 females, respectively. Mean age, history of intrauterine device (IUD) insertion and inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein (CRP) and CA-125 levels, were higher in the TOA group than the non-TOA group. Independent factors that predicted TOA were older age, IUD insertion, increased CRP and CA-125, and chlamydia infection. CA-125 was found to have the highest predictive value for TOA. TOA size was associated with increased surgical therapy compared to patients with smaller abscesses. CONCLUSIONS: Increased age, IUD insertion, chlamydia infection, and increased CRP and CA-125 level were the independent factors predictive of TOA in acute PID. These predictive values will be expected to help decrease gynecological morbidity by early diagnosis and appropriate treatment of TOA. © 2015 S. Karger AG, Basel.

MicroRNAs as potential biomarkers for noninvasive detection of fetal trisomy 21.

PURPOSE: The objective of this study was to discover a panel of microRNAs (miRNAs) as potential biomarkers for noninvasive prenatal testing (NIPT) of trisomy 21 (T21) and to predict the biological functions of identified biomarkers using bioinformatics tools. METHODS: Using microarray-based genome-wide expression profiling, we compared the expression levels of miRNAs in whole blood samples from non-pregnant women, whole blood samples from pregnant women with euploid or T21 fetuses, and placenta samples from euploid or T21 fetuses. We analyzed the differentially expressed miRNAs according to disease and tissue type (P value <0.05 and two-fold expression change). To predict functions of target genes of miRNAs, the functional annotation tools were used. RESULTS: We identified 299 miRNAs which reasonably separate the whole blood from the placenta. Among the identified miRNAs, 150 miRNAs were up-regulated in the placenta, and 149 miRNAs were down-regulated. Most of the up-regulated miRNAs in the placenta were members of the mir-498, mir-379, and mir-127 clusters. Among the up-regulated miRNAs in the placenta, mir-1973 and mir-3196 were expressed at higher levels in the T21 placenta than in the euploid placenta. The two miRNAs potentially regulate 203 target genes that are involved in development of brain, central nervous system, and nervous system. The genes are significantly associated with T21-related disorder such as congenital abnormalities, mental disorders, and nervous system diseases. CONCLUSIONS: Our study indicates placenta-specific miRNAs that may be potential biomarkers for NIPT of fetal T21 and provides new insights into the molecular mechanisms of T21 via regulation of miRNAs.

Quantification and Application of Potential Epigenetic Markers in Maternal Plasma of Pregnancies with Hypertensive Disorders.

The aim of this study was to evaluate quantitative aberrations of novel fetal-specific epigenetic markers in maternal plasma of pregnancies with hypertensive disorders. We compared the concentrations of DSCR3, RASSF1A, and SRY as cell-free fetal DNA markers in 188 normal pregnancies, 16 pregnancies with early-onset preeclampsia (EO-PE), 47 pregnancies with late-onset preeclampsia (LO-PE), and 29 pregnancies with gestational hypertension (GH). The concentrations of all markers were significantly correlated with gestational age (p < 0.001 for all). Strong positive correlations were also observed between DSCR3 and SRY (r = 0.471, p < 0.001), as well as between RASSF1A and SRY (r = 0.326, p = 0.015) and between DSCR3 and RASSF1A (r = 0.673, p < 0.001). The concentrations of DSCR3 and RASSF1A in the EO-PE were significantly higher at 24-32 weeks and onwards (p < 0.05 for both). In the LO-PE, DSCR3 and RASSF1A concentrations were significantly higher only at 33-41 weeks compared with the controls. The concentrations of all markers in the GH group were not significantly different from those in the control group. This study is the first demonstration that DSCR3 is a novel epigenetic marker that can be an alternative to the RASSF1A for the prediction of EO-PE.

Multiple recognition of RXLR effectors is associated with nonhost resistance of pepper against Phytophthora infestans.

Nonhost resistance (NHR) is a plant immune response to resist most pathogens. The molecular basis of NHR is poorly understood, but recognition of pathogen effectors by immune receptors, a response known as effector-triggered immunity, has been proposed as a component of NHR. We performed transient expression of 54 Phytophthora infestansRXLR effectors in pepper (Capsicum annuum) accessions. We used optimized heterologous expression methods and analyzed the inheritance of effector-induced cell death in an F2 population derived from a cross between two pepper accessions. Pepper showed a localized cell death response upon inoculation with P. infestans, suggesting that recognition of effectors may contribute to NHR in this system. Pepper accessions recognized as many as 36 effectors. Among the effectors, PexRD8 and Avrblb2 induced cell death in a broad range of pepper accessions. Segregation of effector-induced cell death in an F2 population derived from a cross between two pepper accessions fit 15:1, 9:7 or 3:1 ratios, depending on the effector. Our genetic data suggest that a single or two independent/complementary dominant genes are involved in the recognition of RXLR effectors. Multiple loci recognizing a series of effectors may underpin NHR of pepper to P. infestans and confer resistance durability.

A vapor-phase deposited polymer film to improve the adhesion of electroless-deposited copper layer onto various kinds of substrates.

The adhesion of electrodeposited metal film to polymeric circuit board substrate is one of the key elements to successful miniaturization of electronic devices. However, as the size of the circuit pattern continuously decreases, a novel method is urgently required to increase the adhesion of the metal film on the substrate, especially on the smooth surface, which is critical to decrease the minimum feature size of the metal pattern. In this research, we developed an adhesion promoter layer by depositing metal chelating poly(4-vinylpyridine) (P4VP) film onto various organic and inorganic substrates via initiated chemical vapor deposition process (iCVD) to enhance the adhesion between the electroless deposited copper (Cu) layer and the substrate. The highest peel strength obtained between the electroless deposited Cu layer and P4VP coated substrate was 1.22 kgf/cm. Many advantageous characteristics of the adhesion promoter layer, including extreme thinness, the improved adhesion strength, conformal coverage, scalability of the deposition process, and short process time, will prompt the applicability of this adhesion promoter layer to industrial scale production.

Development of Drug Efficacy Testing Platform for Glomerulonephritis.

We developed a 3D glomeruli tissue chip for glomerulonephritis (GN) testing, featuring a gravity-driven glomerular filtration barrier (GFB) with human podocytes and endothelial cells with a bidirectional flow in the bottom channel. Using puromycin-induced GN, we observed decreased cell viability, increased albumin permeability, and reduced WT1 and nephrin compared to the normal GFB. Tacrolimus restored cell viability, reduced albumin permeability, and increased WT1 expression. Using serum from five membranous nephropathy (MN) patients, we created MN models using a GFB-mimicking chip. A notable decline in cell viability was observed in the serum-induced MN1 and MN2 models. However, tacrolimus restored it. Albumin permeability was reduced in the MN1, MN2, and MN5 models by tacrolimus treatment. MN1 displayed the best clinical response to tacrolimus, exhibiting increased expression of WT1 in chip-based evaluations after tacrolimus treatment. We successfully evaluated the efficacy of tacrolimus using puromycin-induced and serum-induced GN models on a chip that mimicked the structure and function of the GFB. The GFB-mimicking chip holds promise as a personalized platform for assessing drug efficacy using patient serum samples.

Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.

Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration-time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP.

Effective detection of fetal sex using circulating fetal DNA in first-trimester maternal plasma.

The aim of this study was to develop a simple and effective method for noninvasively detecting fetal sex using circulating fetal DNA from first-trimester maternal plasma. A study was conducted with maternal plasma collected from 203 women between 5 and 12 wk of gestation. The presence of circulating fetal DNA was confirmed by a quantitative methylation-specific polymerase chain reaction of the unmethylated-PDE9A gene (U-PDE9A). Multiplex real-time PCR was used to simultaneously quantify the amount of DYS14 and GAPDH in maternal plasma. The results were confirmed by phenotype at birth. Pregnancy outcomes and U-PDE9A concentrations were obtained in all cases, including 99 male-bearing and 104 female-bearing participants. At equivalent specificity (100%), the false-negative rate was 9.1% for DYS14 quantification cycle, 7.1% for DYS14 concentration, and 0.0% for the concentration ratio of DYS14/GAPDH, respectively. In male-bearing participants, DYS14, U-PDE9A, and GAPDH concentrations were significantly lower in the false-negative case than in correct case (P<0.001 in all). Moreover, DYS14, U-PDE9A, and GAPDH concentrations showed significantly positive associations with each other (P≤0.001 in all). The ratio of DYS14/GAPDH in maternal plasma was an effective biomarker for noninvasive fetal sex detection during the first trimester, indicating that it could be useful for clinical application.

Incidental Extramammary Findings on Preoperative Breast MRI in Breast Cancer Patients: A Pictorial Essay.

Breast cancer is one of the most common cancers and causes several complications in females. Currently, MRI is a necessary method for preoperative studies in patients with breast cancer. A high frequency of breast MRI can lead to an increase in the number of incidental extramammary findings. Moreover, it can provide accurate preoperative workup; therefore, the prognosis of patients can be improved. Herein, we provide several extramammary findings, including the mediastinum, lung, upper abdomen, bone, and soft tissue, correlating with US, chest CT, liver MRI, PET-CT, and bone scan.

Comparison between Real-Time Ultrasound-guided Percutaneous Dilatational Tracheostomy and Surgical Tracheostomy in critically ill Patients: A Randomized Controlled Trial.

OBJECTIVES: Tracheostomy is an important procedure for critically ill patients in the intensive care unit (ICU), and percutaneous dilatational tracheostomy (PDT) has gained popularity due to its safety and effectiveness. However, there are limited data comparing ultrasound-guided PDT (US-PDT) with surgical tracheostomy (ST). In our previous study, we reported that US-PDT had similar safety and effectiveness to ST, with a shorter procedure time. However, the study design was retrospective, and the sample size was small. Therefore, we conducted a randomized controlled trial to demonstrate the safety and efficacy of US-PDT compared to ST. METHODS: A total of 70 patients who underwent either US-PDT (n=35) or ST (n=35) were enrolled in the study between October 20, 2020 and July 26, 2022. The patients were randomly assigned to their respective procedures. The data collected included patient clinical characteristics, procedure time and details, complications, duration of ICU stay, time taken for weaning from mechanical ventilation, and hospital mortality. RESULTS: The procedure time of US-PDT was shorter than that of ST (4.0±2.2 minutes vs. 10.1±4.6 minutes). The incision length of US-PDT was also shorter than that of ST (1.5±0.5 cm vs. 1.8±0.4 cm). There were no statistically significant differences in demographics, procedure details, complications, length of ICU stay, ventilator weaning time, and hospital mortality. CONCLUSION: US-PDT has a similar complication rate and shorter procedure time compared with ST. It can be safely and effectively performed in critically ill patients and can serve as a potential alternative to ST.

The Wnt/ß-catenin signaling pathway plays a role in drug-induced liver injury by regulating cytochrome P450 2E1 expression.

Drug-induced liver injury (DILI) is a major cause of acute liver failure and drug withdrawal. Cytochrome P450 (CYP) 2E1 is involved in the metabolism of several drugs, and can induce liver injury through the production of toxic metabolites and the generation of reactive oxygen species. This study aimed to elucidate the role of Wnt/ß-catenin signaling in CYP2E1 regulation for drug-induced hepatotoxicity. To achieve this, mice were administered cisplatin or acetaminophen (APAP) 1 h after treatment with the CYP2E1 inhibitor dimethyl sulfoxide (DMSO), and histopathological and serum biochemical analyses were performed. APAP treatment induced hepatotoxicity, as evidenced by an increase in liver weight and serum ALT levels. Moreover, histological analysis indicated severe injury, including apoptosis, in the liver tissue of APAP-treated mice, which was confirmed by TUNEL assay. Additionally, APAP treatment suppressed the antioxidant capacity of the mice and increased the expression of the DNA damage markers γ-H2AX and p53. However, these effects of APAP on hepatotoxicity were significantly attenuated by DMSO treatment. Furthermore, the activation of Wnt/ß-catenin signaling using the Wnt agonist CHIR99021 (CHIR) increased CYP2E1 expression in rat liver epithelial cells (WB-F344), whereas treatment with the Wnt/ß-catenin antagonist IWP-2 inhibited nuclear ß-catenin and CYP2E1 expression. Interestingly, APAP-induced cytotoxicity in WB-F344 cells was exacerbated by CHIR treatment and suppressed by IWP-2 treatment. Overall, these results showed that the Wnt/ß-catenin signaling is involved in DILI through the upregulation of CYP2E1 expression by directly binding the transcription factor ß-cat/TCF to the Cyp2e1 promoter, thus exacerbating DILI. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00180-6.