Elevated white blood cell count and long-term clinical outcomes of patients with vasospastic angina.

OBJECTIVES: Inflammation is known as one of key pathophysiologic mechanisms of coronary artery disease. We aimed to investigate the relationship between white blood cell (WBC) count and long-term clinical outcomes of patients with vasospastic angina (VA). METHODS: A total of 823 patients who were diagnosed as VA without significant coronary lesion by coronary angiography with ergonovine provocation test were enrolled for analysis. Patients were divided according to WBC count tertile at the time of diagnosis: group I, tertile 1 and 2 (n = 546, <7490/ml); group II, tertile 3 (n = 277, ≥7490/ml). Primary outcome was defined as major adverse cardiovascular events (MACE), a composite outcome of all-cause death, cardiac death, myocardial infarction (MI), readmission due to cardiac symptoms, and revascularization. RESULTS: Median follow-up duration was 4.3 years. No significant difference of primary outcome was observed between group I and group II (14.7% vs. 20.2%, hazard ratio (HR) 1.29, confidence interval (CI) 0.90-1.83, P = 0.162), while incidence of cardiac death and MI was significantly higher in group II (1.5% vs. 4.3%, HR 2.86, CI 1.14-7.17), P = 0.025). In multivariate Cox regression model, elevated WBC count at the time of diagnosis of VA was an independent predictor of MI (HR 3.43, CI 1.02-11.59, P = 0.047). CONCLUSION: Elevated WBC count at the time of diagnosis was associated with a significantly increased risk of cardiac death and MI during long-term follow-up in VA patients.

Intrahepatic immunoglobulin a complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of hepatocellular carcinoma.

BACKGROUND AND AIMS: Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment (TME). Immunoglobulin A (IgA) contributes to inflammation and dismantling anti-tumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in the TME of hepatocellular carcinoma (HCC). APPROACH AND RESULTS: CAF dynamics in HCC TME were analyzed via single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of advanced HCC patients treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels (p<0.05). Single-cell analysis showed that sub-cluster proportions in the CAF-fibroblast activation protein-α (FAP) matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of FAP in the CD68+ cells from patients with high serum IgA levels (p<0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 (PD-L1) expression levels than those in mock-treated CAFs (p<0.05). Co-culture with CAFs attenuated cytotoxic function of activated CD8+ T cells. Interestingly, activated CD8+ T cells co-cultured with IgA-treated CAFs exhibited increased programmed death-1 (PD-1) expression levels than those co-cultured with mock-treated CAFs (p<0.05). CONCLUSIONS: Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T cell function. Our study highlighted their potential roles in tumor progression and immune suppression.

Validation of Korean Olfactory Questionnaire for Perioperative Olfactory Assessment in Endoscopic Endonasal Skull Base Surgery.

Objective: To analyze changes in olfactory function after endoscopic endonasal skull base surgery and compare performance of the olfactory questionnaire with those of conventional psychophysical tests. Methods: Patients were classified into 5 categories for olfactory function evaluation (normal, mild hyposmia, moderate hyposmia, severe hyposmia, and anosmia) based on a self-assessment. Patients also underwent the butanol threshold test (BTT), Cross-Cultural Smell Identification Test (CCSIT), and 11-item olfactory questionnaire. Subjects with normosmia preoperatively and who were followed up at least 6 months after surgery were analyzed. Receiver operating characteristic curves and confusion matrix analysis were performed for BTT, CCSIT, and olfactory questionnaire to compare their diagnostic abilities. The effects of age, preoperative olfaction, septal flap, tumor pathology, and tumor size on postoperative olfaction were evaluated using multivariate linear regression analysis. Results: Data from 108 patients were analyzed. Postoperative changes in the olfactory questionnaire were significantly associated with changes in the BTT and CCSIT. The area under the curve for postoperative self-olfactory function classification was highest for olfactory questionnaire (0.894), followed by BTT (0.767) and CCSIT (0.688). Patient age at the time of surgery and preoperative BTT score were significantly related to postoperative olfactory outcomes. Conclusion: The olfactory questionnaire correlated well with conventional psychosomatic olfactory function tests. In combination with clinical parameters and preoperative psychosomatic olfactory function tests, the olfactory questionnaire is suitable for assessing subjective olfactory function after endoscopic endonasal skull base surgery.

Treatment Outcome of Olfactory Neuroblastoma: A Multicenter Study by the Korean Sinonasal Tumor and Skull Base Surgery Study Group.

Objectives: Due to the rarity of olfactory neuroblastoma (ONB), there is an ongoing debate about optimal treatment strategies, especially for early staged or locally advanced cases. Therefore, our study aims to explore experiences from multiple centers, focusing on factors that influence the oncological outcomes of ONB. Methods: We retrospectively analyzed 195 ONB patients treated at nine tertiary hospitals in South Korea between December 1992 and December 2019. Kaplan-Meier survival analysis was used to evaluate oncological outcomes, and the Cox proportional hazards regression model was employed to analyze prognostic factors for survival outcomes. Furthermore, we conducted 1:1 nearest-neighbor matching to investigate differences in clinical outcomes according to the use of neoadjuvant chemotherapy. Results: In our cohort, the 5-year overall survival rate (OS) was 78.6%, and the 5-year disease-free survival rate (DFS) was 62.4%. The Cox proportional hazards model revealed that the mKadish stage and Dulguerov T status were significant for DFS, while the mKadish stage and Hyams grade were identified as prognostic factors for OS. The subgroup analyses indicated a trend toward improved 5-year DFS with dural resection in mKadish A and B cases, even though that result was statistically insignificant. Induction chemotherapy did not provide a survival benefit in this study after matching for the mKadish stage and nodal status. Conclusion: Clinical staging and pathologic grading are important prognostic factors in ONB. Dural resection in mKadish A and B did not show a significant survival benefit. Induction chemotherapy did not show a survival benefit, even after stage matching.

Treatment outcome and prognostic factors of inverted papilloma involving the frontal sinus.

Objectives: This study aimed to evaluate the characteristics and treatment outcomes of inverted papillomas involving the frontal sinus. Methods: Patients treated for inverted papilloma involving the frontal sinus between 2003 and 2020 were reviewed. Tumors were classified based on their extent (Extent 1: partially encroaching on the frontal sinus; Extent 2: completely filling the frontal sinus; Extent 3: eroding bony borders beyond the frontal sinus) and site of origin (Origin 1: originating outside the frontal sinus and prolapsing into the frontal sinus; Origin 2: originating from the frontal sinus walls medial to the vertical plane of the lamina papyracea; Origin 3: originating from the frontal sinus walls lateral to the vertical plane of the lamina papyracea). Treatment outcomes including tumor recurrence and patency of the frontal recess were analyzed according to tumor characteristics and surgical treatment modalities. Results: A total of 49 surgical cases were analyzed. Extent 1 were the most common type (n = 27), followed by Extent 2 (n = 15), and Extent 3 (n = 7). The most common sites of origin were Origin 1 (n = 23), followed by Origin 2 (n = 15), and Origin 3 (n = 11). Overall, there were nine recurrences (18.4%). Recurrence was not associated with tumor extent, whereas tumor origin, particularly Origin 3 was associated with higher recurrence; 1/23 (4.3%) for Origin 1, 3/15 (20.0%) for Origin 2, and 5/11 (45.5%) for Origin 3 (Log-rank p < .001). Draf III frontal sinusotomy was associated with in the highest patency rate (84.6%) during the follow-up. Conclusion: The recurrence rate of frontal sinus inverted papilloma depends on tumor origin rather than the extent of the tumor. In particular, lesions originating from the frontal sinus lateral to the lamina papyracea recur frequently. Draf III frontal sinusotomy can achieve patent frontal recess allowing active surveillance. Level of Evidence: IV.

In-Home Smartphone-Based Prediction of Obstructive Sleep Apnea in Conjunction With Level 2 Home Polysomnography.

Importance: Consumer-level sleep analysis technologies have the potential to revolutionize the screening for obstructive sleep apnea (OSA). However, assessment of OSA prediction models based on in-home recording data is usually performed concurrently with level 1 in-laboratory polysomnography (PSG). Establishing the predictability of OSA using sound data recorded from smartphones based on level 2 PSG at home is important. Objective: To validate the performance of a prediction model for OSA using breathing sound recorded from smartphones in conjunction with level 2 PSG at home. Design, Setting, and Participants: This diagnostic study followed a prospective design, involving participants who underwent unattended level 2 home PSG. Breathing sounds were recorded during sleep using 2 smartphones, one with an iOS operating system and the other with an Android operating system, simultaneously with home PSG in participants' own home environment. Participants were 19 years and older, slept alone, and had either been diagnosed with OSA or had no previous diagnosis. The study was performed between February 2022 and February 2023. Main Outcomes and Measures: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the predictive model based on the recorded breathing sounds. Results: Of the 101 participants included during the study duration, the mean (SD) age was 48.3 (14.9) years, and 51 (50.5%) were female. For the iOS smartphone, the sensitivity values at apnea-hypopnea index (AHI) levels of 5, 15, and 30 per hour were 92.6%, 90.9%, and 93.3%, respectively, with specificities of 84.3%, 94.4%, and 94.4%, respectively. Similarly, for the Android smartphone, the sensitivity values at AHI levels of 5, 15, and 30 per hour were 92.2%, 90.0%, and 92.9%, respectively, with specificities of 84.0%, 94.4%, and 94.3%, respectively. The accuracy for the iOS smartphone was 88.6%, 93.3%, and 94.3%, respectively, and for the Android smartphone was 88.1%, 93.1%, and 94.1% at AHI levels of 5, 15, and 30 per hour, respectively. Conclusions and Relevance: This diagnostic study demonstrated the feasibility of predicting OSA with a reasonable level of accuracy using breathing sounds obtained by smartphones during sleep at home.

PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia.

Cerebral ischemia induces massive mitochondrial damage, leading to neuronal death. The elimination of damaged mitochondria via mitophagy is critical for neuroprotection. Here we show that the level of PA2G4/EBP1 (proliferation-associated 2G4) was notably increased early during transient middle cerebral artery occlusion and prevented neuronal death by eliciting cerebral ischemia-reperfusion (IR)-induced mitophagy. Neuron-specific knockout of Pa2g4 increased infarct volume and aggravated neuron loss with impaired mitophagy and was rescued by introduction of adeno-associated virus serotype 2 expressing PA2G4/EBP1. We determined that PA2G4/EBP1 is ubiquitinated on lysine 376 by PRKN/PARKIN on the damaged mitochondria and interacts with receptor protein SQSTM1/p62 for mitophagy induction. Thus, our study suggests that PA2G4/EBP1 ubiquitination following cerebral IR-injury promotes mitophagy induction, which may be implicated in neuroprotection.Abbreviations: AAV: adeno-associated virus; ACTB: actin beta; BNIP3L/NIX: BCL2 interacting protein 3 like; CA1: Cornu Ammonis 1; CASP3: caspase 3; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DMSO: dimethyl sulfoxide; PA2G4/EBP1: proliferation-associated 2G4; FUNDC1: FUN14 domain containing 1; IB: immunoblotting; ICC: immunocytochemistry; IHC: immunohistochemistry; IP: immunoprecipitation; MCAO: middle cerebral artery occlusion; MEF: mouse embryonic fibroblast; OGD: oxygen-glucose deprivation; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced kinase 1; RBFOX3/NeuN: RNA binding fox-1 homolog 3; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I; WT: wild-type.

Differences in Clinical and Immunological Characteristics According to the Various Criteria for Tissue Eosinophilia in Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES: Several criteria exist for classifying chronic rhinosinusitis with nasal polyps (CRSwNP) as eosinophilic or non-eosinophilic. This study attempted to evaluate several criteria for defining eosinophilic CRSwNP from clinical and immunological perspectives. METHODS: A cohort of 84 patients (73 patients with CRSwNP and 11 control patients) was retrospectively analyzed. Patients were divided into eosinophilic and non-eosinophilic CRSwNP based on four different criteria: eosinophils (EOS) accounting for more than 20% of the total inflammatory cells; ≥70 EOS per high-power field (HPF); >55 EOS/HPF; and ≥10 EOS/HPF. Preoperative clinical characteristics, the immunological profiles of 14 cytokines from nasal tissue, and postoperative outcomes were compared between eosinophilic and non-eosinophilic CRSwNP based on each criterion. These criteria were immunologically validated by using 14 cytokines to predict the performance of tissue eosinophilia with a random forest model. RESULTS: Patients with eosinophilic CRSwNP were significantly older when the criterion of ≥10 EOS/HPF or EOS >20% was used. The number of patients with aspirin intolerance was significantly higher in eosinophilic CRSwNP based on the criterion of EOS >20%. From an immunological perspective, non-type 2 inflammatory cytokines were significantly higher in non-eosinophilic CRSwNP with the criterion of EOS >20% of the total inflammatory cells. In addition, the criterion of EOS >20% of the total inflammatory cells resulted in the best prediction of eosinophilic CRSwNP, with an accuracy of 88.10% and area under the curve of 0.94. CONCLUSION: Clinical and immunological characteristics were different between eosinophilic and non-eosinophilic CRSwNP depending on a variety of criteria, and the. RESULTS: of this study should be taken into account when choosing the criterion for defining eosinophilic CRSwNP and interpreting the data accordingly.

How to objectively measure snoring: a systematic review.

PURPOSE: Snoring is the most common symptom of obstructive sleep apnea. Various objective methods of measuring snoring are available, and even if the measurement is performed the same way, communication is difficult because there are no common reference values between the researcher and clinician with regard to intensity and frequency, among other variables. In other words, no consensus regarding objective measurement has been reached. This study aimed to review the literature related to the objective measurement of snoring, such as measurement devices, definitions, and device locations. METHODS: A literature search based on the PubMed, Cochrane, and Embase databases was conducted from the date of inception to April 5, 2023. Twenty-nine articles were included in this study. Articles that mentioned only the equipment used for measurement and did not include individual details were excluded from the study. RESULTS: Three representative methods for measuring snoring emerged. These include (1) a microphone, which measures snoring sound; (2) piezoelectric sensor, which measures snoring vibration; and (3) nasal transducer, which measures airflow. In addition, recent attempts have been made to measure snoring using smartphones and applications. CONCLUSION: Numerous studies have investigated both obstructive sleep apnea and snoring. However, the objective methods of measuring snoring and snoring-related concepts vary across studies. Consensus in the academic and clinical communities on how to measure and define snoring is required.

Hollow porous carbon nanospheres containing polar cobalt sulfide (Co9S8) nanocrystals as electrocatalytic interlayers for the reutilization of polysulfide in lithium-sulfur batteries.

HYPOTHESIS: The introduction of functional interlayers for efficient anchoring of lithium polysulfides has received significant attention worldwide. EXPERIMENTS: A facile wet-chemical method was adopted to obtain hollow porous carbon nanospheres (HPCNSs) impregnated with metallic and polar cobalt sulfide (Co9S8) nanocrystals (abbreviated as "Co9S8@HPCNS"). The prepared nanocrystals were employed as electrocatalytic interlayers via separator coating for the efficient capture and reutilization of polysulfide species in Li-S batteries. The HPCNSs were synthesized via the polymerization method followed by carbonization and template removal. The Co9S8 nanocrystals were impregnated inside the HPCNSs, followed by heat treatment in a reducing atmosphere. FINDINGS: The porous structure of the CNS enables the efficient percolation of the electrolyte, in addition to accommodating unwanted volume fluctuations during redox processes. Furthermore, the metallic Co9S8 nanocrystals improve the electronic conductivity and enhance the polarity of the CNS towards the polysulfide. Correspondingly, the Li-S cells featuring Co9S8@HPCNS as electrocatalytic interlayers and regular sulfur (S) electrodes display improved electrochemical performance such as reasonable rate performance and prolonged cycling stability at different current rates (0.1, 0.5, and 1.0 C). Therefore, we anticipate that the rational design strategy proposed herein will provide significant insights into the synthesis of advanced materials for various energy storage applications.

Corrigendum: Intrahepatic infiltration of activated CD8+ T cells and mononuclear phagocyte is associated with idiosyncratic drug-induced liver injury.

[This corrects the article DOI: 10.3389/fimmu.2023.1138112.].

Protective effects of cell permeable Tat-PIM2 protein on oxidative stress induced dopaminergic neuronal cell death.

Background: Oxidative stress is considered as one of the main causes of Parkinson's disease (PD), however the exact etiology of PD is still unknown. Although it is known that Proviral Integration Moloney-2 (PIM2) promotes cell survival by its ability to inhibit formation of reactive oxygen species (ROS) in the brain, the precise functional role of PIM2 in PD has not been fully studied yet. Objective: We investigated the protective effect of PIM2 against apoptosis of dopaminergic neuronal cells caused by oxidative stress-induced ROS damage by using the cell permeable Tat-PIM2 fusion protein in vitro and in vivo. Methods: Transduction of Tat-PIM2 into SH-SY5Y cells and apoptotic signaling pathways were determined by Western blot analysis. Intracellular ROS production and DNA damage was confirmed by DCF-DA and TUNEL staining. Cell viability was determined by MTT assay. PD animal model was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and protective effects were examined using immunohistochemistry. Results: Transduced Tat-PIM2 inhibited the apoptotic caspase signaling and reduced the production of ROS induced by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells. Furthermore, we confirmed that Tat-PIM2 transduced into the substantia nigra (SN) region through the blood-brain barrier and this protein protected the Tyrosine hydroxylase-positive cells by observation of immunohistostaining. Tat-PIM2 also regulated antioxidant biomolecules such as SOD1, catalase, 4-HNE, and 8-OHdG which reduce the formation of ROS in the MPTP-induced PD mouse model. Conclusion: These results indicated that Tat-PIM2 markedly inhibited the loss of dopaminergic neurons by reducing ROS damage, suggesting that Tat-PIM2 might be a suitable therapeutic agent for PD.

Echinochrome A Prevents Diabetic Nephropathy by Inhibiting the PKC-Iota Pathway and Enhancing Renal Mitochondrial Function in db/db Mice.

Echinochrome A (EchA) is a natural bioproduct extracted from sea urchins, and is an active component of the clinical drug, Histochrome®. EchA has antioxidant, anti-inflammatory, and antimicrobial effects. However, its effects on diabetic nephropathy (DN) remain poorly understood. In the present study, seven-week-old diabetic and obese db/db mice were injected with Histochrome (0.3 mL/kg/day; EchA equivalent of 3 mg/kg/day) intraperitoneally for 12 weeks, while db/db control mice and wild-type (WT) mice received an equal amount of sterile 0.9% saline. EchA improved glucose tolerance and reduced blood urea nitrogen (BUN) and serum creatinine levels but did not affect body weight. In addition, EchA decreased renal malondialdehyde (MDA) and lipid hydroperoxide levels, and increased ATP production. Histologically, EchA treatment ameliorated renal fibrosis. Mechanistically, EchA suppressed oxidative stress and fibrosis by inhibiting protein kinase C-iota (PKCι)/p38 mitogen-activated protein kinase (MAPK), downregulating p53 and c-Jun phosphorylation, attenuating NADPH oxidase 4 (NOX4), and transforming growth factor-beta 1 (TGFß1) signaling. Moreover, EchA enhanced AMPK phosphorylation and nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) signaling, improving mitochondrial function and antioxidant activity. Collectively, these findings demonstrate that EchA prevents DN by inhibiting PKCι/p38 MAPK and upregulating the AMPKα/NRF2/HO-1 signaling pathways in db/db mice, and may provide a therapeutic option for DN.

Inflammatory Endotypes of Chronic Rhinosinusitis in the Korean Population: Distinct Expression of Type 3 Inflammation.

PURPOSE: Cluster analyses on inflammatory markers of chronic rhinosinusitis (CRS) in Asians from multicenter data are lacking. This multicenter study aimed to identify the endotypes of CRS in Koreans and to evaluate the relationship between the endotypes and clinical parameters. METHODS: Nasal tissues were obtained from patients with CRS and controls who underwent surgery. The endotypes of CRS were investigated by measuring interleukin (IL)-5, interferon (IFN)-γ, IL-17A, IL-22, IL-1ß, IL-6, IL-8, matrix metalloproteinase-9, eotaxin-3, eosinophil cationic protein, myeloperoxidase (MPO), human neutrophil elastase (HNE), periostin, transforming growth factor-ß1, total immunoglobulin E (IgE), and staphylococcal enterotoxin (SE)-specific IgE. We performed hierarchical cluster analysis and evaluated the phenotype, comorbidities, and Lund-Mackay computed tomography (LM CT) score in each cluster. RESULTS: Five clusters and 3 endotypes were extracted from 244 CRS patients: cluster 1 had no upregulated mediators compared to the other clusters (mild mixed inflammatory CRS); clusters 2, 3, and 4 had higher concentrations of neutrophil-associated mediators including HNE, IL-8, IL-17A, and MPO (T3 CRS); and cluster 5 had higher levels of eosinophil-associated mediators (T2 CRS). SE-specific IgE was undetectable in T3 CRS and had low detectable levels (6.2%) even in T2 CRS. The CRS with nasal polyps (CRSwNP) phenotype and LM CT scores showed no significant differences between T2 and T3 CRS, while the incidence of comorbid asthma was higher in T2 CRS than T3 CRS. In T3 clusters, higher levels of neutrophilic markers were associated with disease severity and CRSwNP phenotype. CONCLUSIONS: In Koreans, there is a distinct T3 CRS endotype showing a high proportion of CRSwNP and severe disease extent, along with T2 CRS.

Pharmacologic Activation of Angiotensin-Converting Enzyme II Alleviates Diabetic Cardiomyopathy in db/db Mice by Reducing Reactive Oxidative Stress.

BACKGRUOUND: Diabetes mellitus is one of the most common chronic diseases worldwide, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy (DCM) is a phenomenon characterized by a deterioration in cardiac function and structure, independent of vascular complications. Among many possible causes, the renin-angiotensin-aldosterone system and angiotensin II have been proposed as major drivers of DCM development. In the current study, we aimed to investigate the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2) on DCM. METHODS: The ACE2 activator diminazene aceturate (DIZE) was administered intraperitoneally to male db/db mice (8 weeks old) for 8 weeks. Transthoracic echocardiography was used to assess cardiac mass and function in mice. Cardiac structure and fibrotic changes were examined using histology and immunohistochemistry. Gene and protein expression levels were examined using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Additionally, RNA sequencing was performed to investigate the underlying mechanisms of the effects of DIZE and identify novel potential therapeutic targets for DCM. RESULTS: Echocardiography revealed that in DCM, the administration of DIZE significantly improved cardiac function as well as reduced cardiac hypertrophy and fibrosis. Transcriptome analysis revealed that DIZE treatment suppresses oxidative stress and several pathways related to cardiac hypertrophy. CONCLUSION: DIZE prevented the diabetes mellitus-mediated structural and functional deterioration of mouse hearts. Our findings suggest that the pharmacological activation of ACE2 could be a novel treatment strategy for DCM.

Intrahepatic infiltration of activated CD8+ T cells and mononuclear phagocyte is associated with idiosyncratic drug-induced liver injury.

Background: Idiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI. Methods: From January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days. Results: The numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days. Conclusions: Activated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.

Associations Between Systemic Inflammatory Markers Based on Blood Cells and Polysomnographic Factors in Obstructive Sleep Apnea.

OBJECTIVES: Systemic inflammation plays a key role in the pathogenesis of obstructive sleep apnea (OSA); however, easy-to-use methods to evaluate the severity of systemic inflammation have yet to be developed. This study investigated the association between systemic inflammation markers that could be derived from the complete blood count (CBC) profile and sleep parameters in a large number of patients with OSA. METHODS: Patients who visited our hospital's Otorhinolaryngology Sleep Clinic between January 2017 and April 2022 underwent polysomnography and routine laboratory tests, including a CBC. Associations between three systemic inflammatory markers-the systemic immune-inflammation index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR)-and polysomnographic and demographic factors including age, sex, body mass index, the apnea-hypopnea index (AHI), the hypopnea index (HI), lowest oxygen saturation (%), the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale, and percentages of non-rapid eye movement (REM) sleep stage 3, REM sleep, and snoring time were analyzed. The inflammation markers were compared among OSA subgroups, and associations were also analyzed in subgroups with different OSA severities. RESULTS: In total, 1,102 patients (968 men and 134 women) were included, and their mean AHI was 33.0±24.3. PSQI was significantly associated with SII (P=0.027). No independent significant factors were identified for the NLR or PLR. Within the simple snoring and mild OSA subgroups, no significant association was found between sleep parameters and the SII. In the severe OSA subgroup, the AHI (P=0.004) and PSQI (P=0.012) were independently associated with the SII. CONCLUSION: Our study analyzed systemic inflammatory markers based on the CBC, a simple, relatively cost-effective test, and showed that the AHI and SII were significantly correlated only in the severe OSA subgroup.

Risk factors for prolonged hospitalization and delayed treatment completion after laparoscopic appendectomy in patients with uncomplicated acute appendicitis.

PURPOSE: We sought to identify the risk factors for prolonged hospitalization and delayed treatment completion after laparoscopic appendectomy in patients with uncomplicated acute appendicitis. METHODS: The study retrospectively analyzed 497 patients who underwent laparoscopic appendectomies for uncomplicated appendicitis between January 2018 and December 2020. The patients were divided into an early discharge group (≤2 days) and a late discharge group (>2 days) based on the length of hospital stay (LOS). The patients were also divided into uneventful and complicated groups according to the need for additional treatment after standard follow-up. RESULTS: Thirty-seven patients (7.4%) were included in the late discharge group. The mean LOS of the late discharge groups was 3.9 days. There were significant differences according to age, preoperative C-reactive protein (CRP), and operative time between the 2 groups. Only operative time was significantly associated with prolonged LOS in multivariate analysis. Thirty-five patients (7.0%) were included in the complicated group. The mean duration of treatment in the uneventful and complicated groups was 7.4 and 25.3 days, respectively. Significant differences existed between the uneventful and complicated groups in preoperative body temperature, preoperative CRP levels, maximal appendix diameter, and the presence of appendicoliths. In multivariate analysis, preoperative CRP levels and maximal appendix diameter were independent predictors of delayed treatment completion. CONCLUSION: Shorter operative time is desirable to ensure minimal hospital stay in patients with uncomplicated appendicitis. Further efforts are needed to ensure that patients with uncomplicated appendicitis do not experience delayed treatment completion after laparoscopic appendectomies.

Tat-Thioredoxin-like protein 1 attenuates ischemic brain injury by regulation of MAPKs and apoptosis signaling.

Thioredoxin-like protein 1 (TXNL1), one of the thioredoxin superfamily known as redox-regulator, plays an essential in maintaining cell survival via various antioxidant and anti-apoptotic mechanisms. It is well known that relationship between ischemia and oxidative stress, however, the role of TXNL1 protein in ischemic damage has not been fully investigated. In the present study, we aimed to determine the protective role of TXNL1 against on ischemic injury in vitro and in vivo using cell permeable Tat-TXNL1 fusion protein. Transduced Tat-TXNL1 inhibited ROS production and cell death in H2O2-exposed hippocampal neuronal (HT-22) cells and modulated MAPKs and Akt activation, and pro-apoptotic protein expression levels in the cells. In an ischemia animal model, Tat-TXNL1 markedly decreased hippocampal neuronal cell death and the activation of astrocytes and microglia. These findings indicate that cell permeable Tat-TXNL1 protects against oxidative stress in vitro and in vivo ischemic animal model. Therefore, we suggest Tat-TXNL1 can be a potential therapeutic protein for ischemic injury. [BMB Reports 2023; 56(4): 234-239].