Anti-inflammatory effects of neuregulin-1 in HaCaT keratinocytes and atopic dermatitis-like mice stimulated with Der p 38.

Neuregulin (NRG)-1 plays fundamental roles in several organ systems after binding to its receptors, ErbB2 and ErbB4. This study examines the role of NRG-1 in atopic dermatitis (AD), a chronic skin disease that causes dryness, pruritus, and inflammation. In mice administered Der p 38, the skin presents AD-like symptoms including filaggrin downregulation and infiltration of neutrophils and eosinophils. Noticeably, there is an increased expression of NRG-1, ErbB2, and ErbB4 in the skin. Upregulation of these proteins is significantly correlated to the clinical skin severity score. In human keratinocyte HaCaT cells, exposure to Der p 38 decreased filaggrin expression, and NRG-1 alone had no effect on the expression. However, co-treatment of Der p 38 with NRG-1 enhanced the filaggrin expression decreased by Der p 38. Pre-treatment with AG879 (an ErbB2 inhibitor) or ErbB4 siRNA blocked the recovery of filaggrin expression in the cells after co-treatment with Der p 38 and NRG-1. Der p 38 treatment enhanced the secretion of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1). Co-treatment of Der p 38 with NRG-1 lowered the cytokine secretion increased by Der p 38, although NRG-1 alone was not effective on cytokine alteration. Neutrophil apoptosis was not altered by NRG-1 or supernatants of cells treated with NRG-1, but the cell supernatants co-treated with Der p 38 and NRG-1 blocked the anti-apoptotic effects of Der p 38-treated supernatants on neutrophils, which was involved in the activation of caspase 9 and caspase 3. Taken together, we determined that NRG-1 has anti-inflammatory effects in AD triggered by Der p 38. These results will pave the way to understanding the functions of NRG-1 and in the future development of AD treatment.

Der p 38 Is a Bidirectional Regulator of Eosinophils and Neutrophils in Allergy.

The house dust mite is the most common cause of allergic diseases, and TLR4 acts as an overarching receptor for allergic responses. This study aimed to identify novel allergen binding to TLR4 in house dust mites and unveil its unique role in allergic responses. Der p 38 was purified and characterized by liquid chromatography tandem mass spectrometry-based peptide mapping. Biolayer interferometry and structure modeling unveiled TLR4-binding activity and the structure of recombinant Der p 38. The allergenicity of Der p 38 was confirmed by a skin prick test, and basophil activation and dot blot assays. The skin prick test identified 24 out of 45 allergic subjects (53.3%) as Der p 38+ subjects. Der p 38-augmented CD203c expression was noted in the basophils of Der p 38+ allergic subjects. In animal experiments with wild-type and TLR4 knockout BALB/c mice, Der p 38 administration induced the infiltration of neutrophils as well as eosinophils and exhibited clinical features similar to asthma via TLR4 activation. Persistent Der p 38 administration induced severe neutrophil inflammation. Der p 38 directly suppressed the apoptosis of allergic neutrophils and eosinophils, and enhanced cytokine production in human bronchial epithelial cells, inhibiting neutrophil apoptosis. The mechanisms involved TLR4, LYN, PI3K, AKT, ERK, and NF-κB. These findings may contribute to a deep understanding of Der p 38 as a bridge allergen between eosinophilic and neutrophilic inflammation in the pathogenic mechanisms of allergy.

The Impact of Omicron Wave on Pediatric Febrile Seizure.

BACKGROUND: The coronavirus disease 2019 (COVID-19) omicron (B.1.1.529) variant reduced the risk of severe disease compared with the original strain and other variants, but it appeared to be highly infectious, which resulted in an exponential increase in confirmed cases in South Korea. As the number of confirmed cases increased, so did the number of pediatric patients' hospitalization. This study aims to evaluate the frequency and clinical features of febrile seizure associated with the COVID-19 omicron variant in children. METHODS: We retrospectively reviewed the medical records of children aged under 18 years with febrile seizure who were tested for COVID-19 from February 2020 to April 2022 at Ajou University Hospital, South Korea. Based on the dominant variants, we divided the period into the pre-omicron (from February 2020 to December 2021) and omicron periods (from January 2022 to April 2022) and compared the clinical characteristics between the two. Also, we compared the clinical characteristics of febrile seizure between COVID-19 positive and negative group during the omicron period. RESULTS: Among the 308 children, 211 patients (9.2 patients/months) and 97 patients (24.3 patients/months) were grouped into pre-omicron and omicron periods, respectively. Compared with the pre-omicron period, patients in the omicron period showed significantly higher mean age (pre-omicron vs. omicron, 22.0 vs. 28.0 months; P = 0.004) and COVID-19 positive results (pre-omicron vs. omicron, 0.5% vs. 62.9%; P < 0.001). As the COVID-19 confirmed cases in the omicron period increased, the number of COVID-19 associated febrile seizure also increased. In the omicron period, 61 children were confirmed to be positive for COVID-19, and COVID-19 positive group showed statistically significant higher mean age (positive vs. negative, 33.0 vs. 23.0 months; P = 0.003) and peak body temperature than the negative group (positive vs. negative, 39.1°C vs. 38.6°C; P = 0.030). Despite the lack of significance, COVID-19 positive group showed longer seizure time, multiple seizure episodes, and higher prevalence of complex febrile seizure. CONCLUSION: The frequency of COVID-19 associated febrile seizure increased in the omicron periods. In addition, in this period, children with febrile seizure diagnosed with COVID-19 had a higher mean age and higher peak body temperature.

Comparison of the Clinical Characteristics of Pediatric Poisoning Patients Who Visited Emergency Department Before and During the COVID-19 Pandemic.

BACKGROUND: We aimed to investigate changes in the clinical characteristics of pediatric poisoning patients who visited the emergency department (ED) before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Poisoning cases below age 18 who visited the ED from January 2018 to December 2021 were retrospectively analysed. The study period was then divided into pre-COVID-19 and COVID-19 pandemic to compare poisoning patterns. RESULTS: During the study period, 86,153 visits to the pediatric ED had been recorded, with 625 patients being included the final analysis. During the COVID-19 period, the proportion of poisoned patients increased from 0.62% to 0.98%. The average age of the patients was higher in the COVID-19 period, with 53.4% of the cases being intentional (pre-COVID-19, 32.5%; P < 0.001). Moreover, 70.4% of poisoning cases during the COVID-19 period were caused by drugs (pre-COVID-19, 60.6%; P = 0.038). More patients underwent decontamination and laboratory investigation during the COVID-19 period than during the previous period (P = 0.007 and P < 0.001, respectively). The length of ED stay and the proportion of hospitalisation were significantly greater during the COVID-19 period. After analysing accidental poisoning cases, we found that antipyretics/nonsteroidal anti-inflammatory drugs and respiratory drugs were more common in the pre-COVID-19 group, whereas iron/vitamins, cardiovascular drugs and hormones were more common in the COVID-19 group. After analysing intentional poisoning cases, we found that 73.6% and 76.4% of the patients in the pre-COVID-19 and COVID-19 group had a history of psychiatric disease, respectively. Although no difference was observed in the frequency of previous first suicide attempts, 19.0% of the patients in the COVID-19 group attempted suicide more than three times. CONCLUSION: During the COVID-19 pandemic, intentional poisoning cases, especially in adolescence, increased and were treated more. Many of the patients with intentional poisoning had a history of mental illness or suicide in the past. Therefore, it seems that policy consideration for mentally vulnerable adolescents during this new pandemic period is necessary.

The effect of oral ondansetron on QT interval in children with acute gastroenteritis; a retrospective observational study.

BACKGROUND: In mildly to moderately dehydrated patients with acute gastroenteritis (AGE), oral rehydration therapy (ORT) is the treatment of choice. Though ondansetron is a very effective antiemetics and leads to succeed ORT, there have been reports QT prolongation in patients using it. We investigated the effect of oral ondansetron on QT interval in mildly to moderately dehydrated children with AGE. METHODS: This retrospective observational study was conducted in a single pediatric emergency department (ED) of a tertiary university hospital. We collected the medical records of patients with a primary diagnosis of AGE who received oral ondansetron and underwent an electrocardiogram between January 2017 and June 2018. A pediatric emergency physician calculated the corrected QT interval (QTc) by Bazett's method, and the calculations were reviewed by a pediatric cardiologist. QTc values before (preQTc) and after (postQTc) ondansetron administration were analyzed. ΔQTc was calculated as the change from preQTc to postQTc. We also investigated any cardiac complications from oral ondansetron. RESULTS: Total 80 patients were included. The mean age of the patients was 53.31 ± 32.42 months, and 45% were male. The mean dose of oral ondansetron was 0.18 ± 0.04 mg/kg. The mean interval from administration of ondansetron to performance of the electrocardiogram was 65 ± 26 min. The mean preQTc was 403.3 ± 24.0 ms, and the mean postQTc was 407.2 ± 26.7 ms. Two patients had a preQTc ≥460 ms, and one patient had a postQTc ≥460 ms. ΔQTc was ≥30 ms in seven patients (8.8%). No ΔQTc was ≥60 ms. No pre- or postQTc was ≥500 ms. No patient had a fatal cardiac arrhythmia after taking ondansetron. CONCLUSION: Oral administration of a single dose of ondansetron in children with AGE did not cause high-risk QTc prolongation or fatal arrhythmia.

Performance of the BIG Score in Predicting Mortality in Normotensive Children With Trauma.

OBJECTIVES: Children have a larger reserve for traumatic hemorrhagic shock, requiring a score that uses physiologic variables other than hypotension. Recently, the BIG score comprising admission base deficit, international normalized ratio, and the Glasgow Coma Scale has been reported to predict traumatic mortality. We aimed to validate the performance of the BIG score in mortality prediction of normotensive children with trauma. METHODS: We reviewed 1046 injured children (<18 years) who visited a Korean academic hospital from 2010 to 2018, excluding those with age-adjusted hypotension. In-hospital mortality, the BIG score and its predicted mortality, Revised Trauma Score, and Pediatric Trauma Score were calculated. We compared areas under the curve (AUCs) for in-hospital mortality of the 3 scores and did in-hospital and BIG-predicted mortalities. RESULTS: Of the 1046 children, 554 were enrolled with a 4.9% in-hospital mortality rate. The median BIG score was higher in the nonsurvivors (6.4 [interquartile range, 4.4-9.2] vs 20.1 [16.5-24.8]; P < 0.001). The AUC of the BIG score was 0.94 (95% confidence interval [CI], 0.92-0.96), which was higher than that of Pediatric Trauma Score (0.87 [95% CI, 0.84-0.90]; P < 0.001). The AUC of the BIG score tended to be higher than that of Revised Trauma Score without statistical significance (0.90 [95% CI, 0.87-0.92]; P = 0.130). We noted a parallel between in-hospital and BIG-predicted mortalities. The hemorrhage-related nonsurvivors showed higher median base deficit and BIG score than did the isolated traumatic brain injury-related ones. CONCLUSIONS: The BIG score can predict mortality with excellent accuracy in normotensive children with trauma.

Der f 38 Is a Novel TLR4-Binding Allergen Related to Allergy Pathogenesis from Dermatophagoides farinae.

It is difficult to treat allergic diseases including asthma completely because its pathogenesis remains unclear. House dust mite (HDM) is a critical allergen and Toll-like receptor (TLR) 4 is a member of the toll-like receptor family, which plays an important role in allergic diseases. The purpose of this study was to characterize a novel allergen, Der f 38 binding to TLR4, and unveil its role as an inducer of allergy. Der f 38 expression was detected in the body and feces of Dermatophagoides farinae (DF). Electron microscopy revealed that it was located in the granule layer, the epithelium layer, and microvilli of the posterior midgut. The skin prick test showed that 60% of allergic subjects were Der f 38-positive. Der f 38 enhanced surface 203c expression in basophils of Der f 38-positive allergic subjects. By analysis of the model structure of Der p 38, the expected epitope sites are exposed on the exterior side. In animal experiments, Der f 38 triggered an infiltration of inflammatory cells. Intranasal (IN) administration of Der f 38 increased neutrophils in the lung. Intraperitoneal (IP) and IN injections of Der f 38 induced both eosinophils and neutrophils. Increased total IgE level and histopathological features were found in BALB/c mice treated with Der f 38 by IP and IN injections. TLR4 knockout (KO) BALB/c mice exhibited less inflammation and IgE level in the sera compared to wild type (WT) mice. Der f 38 directly binds to TLR4 using biolayer interferometry. Der f 38 suppressed the apoptosis of neutrophils and eosinophils by downregulating proteins in the proapoptotic pathway including caspase 9, caspase 3, and BAX and upregulating proteins in the anti-apoptotic pathway including BCL-2 and MCL-1. These findings might shed light on the pathogenic mechanisms of allergy to HDM.

Suppressive effects of S100A8 and S100A9 on neutrophil apoptosis by cytokine release of human bronchial epithelial cells in asthma.

S100A8 and S100A9 are important proteins in the pathogenesis of allergy. Asthma is an allergic lung disease, characterized by bronchial inflammation due to leukocytes, bronchoconstriction, and allergen-specific IgE. In this study, we examined the role of S100A8 and S100A9 in the interaction of cytokine release from bronchial epithelial cells, with constitutive apoptosis of neutrophils. S100A8 and S100A9 induce increased secretion of neutrophil survival cytokines such as MCP-1, IL-6 and IL-8. This secretion is suppressed by TLR4 inhibitor), LY294002, AKT inhibitor, PD98059, SB202190, SP600125, and BAY-11-7085. S100A8 and S100A9 also induce the phosphorylation of AKT, ERK, p38 MAPK and JNK, and activation of NF-κB, which were blocked after exposure to TLR4i, LY294002, AKTi, PD98059, SB202190 or SP600125. Furthermore, supernatants collected from bronchial epithelial cells after S100A8 and S100A9 stimulation suppressed the apoptosis of normal and asthmatic neutrophils. These inhibitory mechanisms are involved in suppression of caspase 9 and caspase 3 activation, and BAX expression. The degradation of MCL-1 and BCL-2 was also blocked by S100A8 and S100A9 stimulation. Essentially, neutrophil apoptosis was blocked by co-culture of normal and asthmatic neutrophils with BEAS-2B cells in the presence of S100A8 and S100A9. These findings will enable elucidation of asthma pathogenesis.

Chaenomeles sinensis Koehne extract suppresses the development of atopic dermatitis-like lesions by regulating cytokine and filaggrin expression in NC/Nga mice.

Chaenomeles sinensis Koehne (CS) has been used in a traditional oriental medicine for treating throat diseases, anaphylaxis, viral infection, and inflammation. This study investigated the underlying mechanism of anti-allergic effect of CS. Leaves of CS plants were dried, powdered, and then underwent extraction with DMSO. Both ELISA and western blotting were performed to evaluate cytokine concentration and the expression and activation of filaggrin and JNK. Five-week-old female NC/Nga mice were used as an AD-like mouse model by treating them with 2,4-dinitrochlorobenzene (DNCB). The secretion of TARC, MCP-1, and IL-8 is increased by TNF-α and IFN-γ in HaCaT cells, and CS extract inhibited the increased production of TARC, MCP-1, and IL-8. TNF-α and IFN-γ suppressed filaggrin expression by activating JNK. CS extract recovered the expression of filaggrin decreased by TNF-α and IFN-γ by blocking the activation of JNK. In vivo experiment, CS administration reduced thickening of the epidermis and infiltration of inflammatory cells into the dermis as compared to DNCB treatment. Moreover, the decrease of filaggrin expression due to DNCB treatment was recovered by CS administration. The serum IgE level was decreased by CS treatment. The levels of IL-4, IL-5, IL-13 and eotaxin in mouse splenocytes increased after treatment with concanavalin A, and the secretions of IL-4, IL-5, IL-13 and eotaxin were lower in the CS-treated group than in the DNCB group. These results may contribute to the development of a CS-based drug for the treatment of atopic dermatitis.

Poncirus Trifoliata (L.) Raf. Extract Inhibits the Development of Atopic Dermatitis-like Lesions in Human Keratinocytes and NC/Nga mice.

This study investigated the anti-allergic effect of Poncirus trifoliata (L.) Raf. (PT) on human keratinocytic HaCaT cells in vitro and on 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like lesions in vivo. The release of TARC, MCP-1, IL-6 and IL-8 is increased by IFN-γ and TNF-α in HaCaT cells, and PT extract suppressed the increased production of TARC, MCP-1, IL-6, and IL-8. PT extract recovered the expression of filaggrin decreased by IFN-γ and TNF-α. in vivo experiment, PT administration decreased the skin severity score, thickening of the epidermis, movement of inflammatory cells into the dermis, and serum IgE level as compared to DNCB treatment. Moreover, the decrease of filaggrin and loricrin induced by DNCB treatment was recovered by PT administration. The levels of IL-4, IL-5, IL-13 and eotaxin in mouse splenocytes increased after treatment with concanavalin A, and the secretions of IL-4, IL-5, IL-13 and eotaxin were lower in the PT-treated group than in the DNCB group. These findings may indicate that PT is useful in drug development for the treatment of AD.

Clinical characteristics of enteroviral meningitis without pleocytosis in children: a retrospective single center observational study in the Republic of Korea.

BACKGROUND: We aimed to study the prevalence of enterovirus (EV) meningitis without the presence of cerebrospinal fluid (CSF) pleocytosis and identify patient factors and clinical features associated with it. METHODS: This was a retrospective analysis of patients aged < 18 years old who were diagnosed with EV meningitis by CSF reverse-transcriptase polymerase chain reaction (RT-PCR) testing between January 2015 and December 2016. Clinical variables were compared with regard to the presence of CSF pleocytosis. RESULTS: A total of 305 patients were enrolled in study; 169 (55.4%) had no pleocytosis. Patients without pleocytosis were younger (median age 2 months vs. 67.0 months, p < 0.01) and had lower white blood cell (WBC) count (median, 8600/mm3 vs. 10,300/mm3, p < 0.01). Also absolute neutrophil (ANC) count were lower than pleocytosis group (median, 4674/mm3 vs. 7600/mm3, p < 0.01). Comparing three age groups, CSF apleocytosis was present in 106 of 128 patients (82.8%) aged ≤3 months, 7 of 13 patients (53.8%) aged 3 months-3 years and 56 of 164 patients (34.1%) aged > 3 years. Younger age groups had higher prevalence of CSF apleocytosis (p < 0.01). In patients aged ≤3 months, 94.5% underwent lumbar puncture within 24 h of symptom onset. The frequency of not having pleocytosis was higher than the frequency of having pleocytosis during peak EV infection prevalent months (summer and fall) (p < 0.01). CONCLUSION: This study shows that EV meningitis in young infants, with early lumbar puncture, or occurring during peak EV meningitis prevalent seasons cannot be solely excluded by pleocytosis. Also, a confirmation test for EV meningitis should be performed using RT-PCR.

Thymus and activation-regulated chemokine (TARC)/CCL17 and IgE are associated with elderly asthmatics.

BACKGROUND: The pathogenesis of asthma, which is an allergic lung disease, is associated with a variety of allergens such as house dust mite, pollen, and mould, IgE containing serum IgE and allergen-specific-IgE, and inflammatory cytokines including thymus and activation-regulated chemokine (TARC)/CCL17. Because aging is an essential factor in the pathogenesis of asthma, we examined biomarkers related to asthmatic subjects depending on age. RESULTS: Physiological indices such as FEV1(forced expiratory capacity in 1 s), FEV1 (% predicted), and FEV1/FVC(forced vital capacity) (%) in asthmatic subjects were lower than those in normal subjects. Total IgE, Der p1 specific IgE, and Der f1 specific IgE were elevated in serum of asthmatics relative to normal individuals. Regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5 in serum and interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein (MCP)-1/CCL2, RANTES, and macrophage inflammatory protein (MIP)-1α/CCL3 in bronchoalveolar lavage fluid (BALF) of asthmatic subjects were higher than in normal individuals. Upon classification of experimental groups depending on age, physiological indices and Der p1-specific IgE (class) were decreased in middle aged adult and elderly adult groups relative to the young adult group. TARC levels in serum were strongly elevated in the elderly adult group relative to the young adult and the middle aged adult groups. TARC in serum was related to total IgE in serum in the elderly adult group. CONCLUSIONS: Taken together, although TARC in serum and BALF is not different between normal and asthmatic individuals, TARC increases in serum of elderly asthmatic subjects. The level of TARC has a positive effect on the level of IgE in the elderly adult group. These findings may help us better understand the relationship of pathogenesis of allergic diseases and aging.

Excessive Cytolytic Responses Predict Tuberculosis Relapse After Apparently Successful Treatment.

BACKGROUND: Currently, there are no tools to accurately predict tuberculosis relapse. This study aimed to determine whether patients who experience tuberculosis relapse have different immune responses to mycobacteria in vitro than patients who remain cured for 2 years. METHODS: Patients with an initial episode of pulmonary tuberculosis were recruited in South Africa. Diluted blood, collected at diagnosis and after 2 and 4 weeks of treatment, was cultured with live Mycobacterium tuberculosis for 6 days, and cellular RNA was frozen. Gene expression in samples from 10 patients who subsequently experienced relapse, confirmed by strain genotyping, was compared to that in samples from patients who remained cured, using microarrays. RESULTS: At diagnosis, expression of 668 genes was significantly different in samples from patients who experienced relapse, compared with expression in patients who remained successfully cured; these differences persisted for at least 4 weeks. Gene ontology and biological pathways analyses revealed significant upregulation of genes involved in cytotoxic cell-mediated killing. Results were confirmed by real-time quantitative reverse-transcription polymerase chain reaction analysis in a wider patient cohort. CONCLUSIONS: These data show that patients who will subsequently experience relapse exhibit altered immune responses, including excessively robust cytolytic responses to M. tuberculosis in vitro, at the time of diagnosis, compared with patients who will achieve durable cure. Together with microbiological and clinical indices, these differences could be exploited in drug development.

Cytokine secreted by S100A9 via TLR4 in monocytes delays neutrophil apoptosis by inhibition of caspase 9/3 pathway.

Dysregulation of neutrophil apoptosis causes pathogenesis and aggravation of allergy. S100A9 exists as one of the proteins in the neutrophils, triggering inflammatory responses by activating the immune cells. In this study, we investigated whether S100A9 affects constitutive neutrophil apoptosis by activating the monocytes in normal and allergic subjects. Supernatant from human monocytic THP-1 cells after treatment with S100A9 suppressed normal neutrophil apoptosis by inhibiting the activations of caspase 9 and caspase 3. S100A9 upregulated the release of MCP-1, IL-6, and IL-8 in THP-1 cells. An increase in cytokine was suppressed by CLI-095, a Toll-like receptor (TLR) 4 inhibitor, PP2, a Src inhibitor, rottlerin, a PKCδ inhibitor, MAP kinase inhibitors, including PD98059, SB202190, and SP600125, and BAY-11-7085, an NF-κB inhibitor. Src, PKCδ, ERK1/2, p38 MAPK, and JNK were phosphorylated by S100A9. The phosphorylation of Src and PKCδ was suppressed by CLI-095, and the activation of ERK1/2, p38 MAPK, and JNK was inhibited by CLI-095, PP2, and rottlerin. S100A9 induced NF-κB activity, and the activation was suppressed by CLI-095, PP2, rottlerin, and MAPK kinase inhibitors. In normal and allergic subjects, supernatant from normal and allergic monocytes after stimulation with S100A9 suppressed normal and allergic neutrophil apoptosis, respectively; MCP-1, IL-6, and IL-8 in the supernatant was increased by S100A9. The cytokine secretion induced by S100A9 is related to TLR4, Src, PKCδ, ERK1/2, p38 MAPK, JNK, and NF-κB. Taken together, S100A9 induces anti-apoptotic effect on normal and allergic neutrophils by increasing cytokine secretion of monocytes. These findings may help us to better understand neutrophil apoptosis regulated by S100A9 and pathogenesis of allergic diseases.

The Protective Effect of INH2BP, a Novel PARP Inhibitor 5-Iodo-6-Amino-1,2-Benzopyrone, Against Hydrogen Peroxide-Induced Apoptosis Through ERK and p38 MAPK in H9c2 Cells.

INH2BP (5-iodo-6-amino-1,2-benzopyrone), a poly-ADP ribose polymerase inhibitor, has been shown to possess anti-cancer, anti-viral, and anti-inflammation properties. The aim of this study was to investigate the protective effect of INH2BP against oxidative stress-induced apoptosis in H9c2 cardiomyoblast cells. While the treatment of H9c2 cardiomyoblasts cells with hydrogen peroxide (H2O2) caused a loss of cell viability and an increase in the number of apoptotic cells, INH2BP significantly protected the cells against H2O2-induced cell death without any cytotoxicity. Our data also shows that INH2BP significantly scavenged intracellular reactive oxygen species (ROS), and markedly enhanced the expression of antioxidant enzymes such as Mn-SOD (superoxide) and Cu/Zn-SOD, and heme oxygenase-1, which was accompanied by the concomitant activation of extracellular regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) phosphorylation in H9c2 cells. The effects of INH2BP on ERK1/2 and p38 MAPK phosphorylation were abrogated by PD98059, an ERK1/2 inhibitor, and SB203580, a p38 inhibitor. In addition, inhibition of ERK1/2 and p38 MAPK by these inhibitors significantly attenuated INH2BP-mediated H9c2 viability as well as cleaved caspases-3, Bax, and Bcl-2 activation. Taken together, these results demonstrate that INH2BP prevents H2O2-induced apoptosis in H9c2 cells by reducing the production of intracellular ROS, regulating apoptotic-related proteins, and the activation of the ERK1/2 and p38 MAPK.

Carbon monoxide-induced cardiomyopathy.

BACKGROUND: Previous reports demonstrated mechanisms of cardiac toxicity in acute carbon monoxide (CO) poisoning. Still, none established CO-induced cardiomyopathy (CMP) as a clinical entity. The aim of this study is to investigate CO-induced CMP in patients with acute CO poisoning in terms of its epidemiology, clinical characteristics, and prognosis. METHODS AND RESULTS: A retrospective study was conducted on consecutive patients who were diagnosed with acute CO poisoning at the emergency department of Ajou University Hospital during the period of 62 month. Six hundred and twenty-six patients were diagnosed with acute CO poisoning. During the initial echocardiography, 19 patients were abnormal: (1) global hypokinesia/akinesia (n=7), (2) regional wall hypokinesia/akinesia [n=12; takotsubo type (n=6), reverse takotsubo type (n=2), non-specific type (n=4)]. The ejection fraction (EF) was 36.3±13.5% (from 15% to 55%) and less than 45% for 14 patients. In the follow-up echocardiography performed within 12 days after the initial performance, most patients were found to have cardiac wall motion abnormalities, and their EF had returned to normal (ie, EF ≥50%). CONCLUSIONS: CO-induced CMP was identified in 3.04% (n=19) of all patients (n=626). It might not be too critical in acute clinical courses of acute CO poisoning because the prognosis seems favorable. Considering the common factors between CO-induced CMP and takotsubo CMP, myocardial stunning subject to a catecholamine surge most likely plays a central role in the development of CO-induced CMP.

Distinct phases of blood gene expression pattern through tuberculosis treatment reflect modulation of the humoral immune response.

BACKGROUND: Accurate assessment of treatment efficacy would facilitate clinical trials of new antituberculosis drugs. We hypothesized that early alterations in peripheral immunity could be measured by gene expression profiling in tuberculosis patients undergoing successful conventional combination treatment. METHODS: Ex vivo blood samples from 27 pulmonary tuberculosis patients were assayed at diagnosis and during treatment. RNA was processed and hybridized to Affymetrix GeneChips, to determine expression of over 47,000 transcripts. RESULTS: There were significant ≥ 2-fold changes in expression of >4000 genes during treatment. Rapid, large-scale changes were detected, with down-regulated expression of 1261 genes within the first week, including inflammatory markers such as complement components C1q and C2. This was followed by slower changes in expression of different networks of genes, including a later increase in expression of B-cell markers, transcription factors, and signaling molecules. CONCLUSIONS: The fast initial down-regulation of expression of inflammatory mediators coincided with rapid killing of actively dividing bacilli, whereas slower delayed changes occurred as drugs acted on dormant bacilli and coincided with lung pathology resolution. Measurement of biosignatures during clinical trials of new drugs could be useful predictors of rapid bactericidal or sterilizing drug activity, and would expedite the licensing of new treatment regimens.

Prognostic Performance of Initial Clinical Examination in Predicting Good Neurological Outcome in Cardiac Arrest Patients Treated with Targeted Temperature Management.

Prognostication studies of cardiac arrest patients have mainly focused on poor neurological outcomes. However, an optimistic prognosis for good outcome could provide both justification to maintain and escalate treatment and evidence-based support to persuade family members or legal surrogates after cardiac arrest. The aim of the study was to evaluate the utility of clinical examinations performed after return of spontaneous circulation (ROSC) in predicting good neurological outcomes in out-of-hospital cardiac arrest (OHCA) patients treated with targeted temperature management (TTM). This retrospective study included OHCA patients treated with TTM from 2009 to 2021. Initial clinical examination findings related to the Glasgow coma scale (GCS) motor score, pupillary light reflex, corneal reflex (CR) and breathing above the set ventilator rate were assessed immediately after ROSC and before the initiation of TTM. The primary outcome was good neurological outcome at 6 months after cardiac arrest. Of 350 patients included in the analysis, 119 (34%) experienced a good neurological outcome at 6 months after cardiac arrest. Among the parameters of the initial clinical examinations, specificity was the highest for the GCS motor score, and sensitivity was the highest for breathing above the set ventilator rate. A GCS motor score of >2 had a sensitivity of 42.0% (95% confidence interval [CI] = 33.0-51.4) and a specificity of 96.5% (95% CI = 93.3-98.5). Breathing above the set ventilator rate had a sensitivity of 84.0% (95% CI = 76.2-90.1) and a specificity of 69.7% (95% CI = 63.3-75.6). As the number of positive responses increased, the proportion of patients with good outcomes increased. Consequently, 87.0% of patients for whom all four examinations were positive experienced good outcomes. As a result, the initial clinical examinations predicted good neurological outcomes with a sensitivity of 42.0-84.0% and a specificity of 69.7-96.5%. When more examinations with positive results are achieved, a good neurological outcome can be expected.

The 30-kDa and 38-kDa antigens from Mycobacterium tuberculosis induce partial maturation of human dendritic cells shifting CD4(+) T cell responses towards IL-4 production.

BACKGROUND: Mycobacterium tuberculosis (Mtb) infections are still a major cause of death among all infectious diseases. Although 99% of individuals infected with Mtb develop a CD4(+) Th1 and CD8(+) T cell mediated immunity as measured by tuberculin skin test, this results only in partial protection and Mtb vaccines are not effective. Deviation of immune responses by pathogens towards a Th2 profile is a common mechanism of immune evasion, typically leading to the persistence of the microbes. RESULTS: Here we tested the stimulatory capacity of selective Mtb antigens on human monocyte-derived dendritic cell (DC) maturation and cytokine production. DC maturation markers CD80, CD86 and CD83 were readily upregulated by H37Ra- and H37Rv-associated antigens, the 30-kDa (from Ag85 B complex) and 38-KDa Mtb antigens only partially induced these markers. All Mtb antigens induced variable levels of IL-6 and low levels of IL-10, there was no release of IL-12p70 detectable. Substantial IL-12p40 production was restricted to LPS or H37Ra and H37Rv preparations. Although the proliferation levels of primary T cell responses were comparable using all the differentially stimulated DC, the 30-kDa and 38-kDa antigens showed a bias towards IL-4 secretion of polarized CD4(+) T cells after secondary stimulation as compared to H37Ra and H37Rv preparations. CONCLUSION: Together our data indicate that 30-kDa and 38-kDa Mtb antigens induced only partial DC maturation shifting immune responses towards a Th2 profile.

A (S)-(+)-decursin derivative, (S)-(+)-3-(3,4-dihydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano[3,2-g]-chromen-3-yl-ester, attenuates the development of atopic dermatitis-like lesions in NC/Nga mice.

(S)-(+)-decursin is a biological coumarin compound isolated from Angelica gigas Nakai. (S)-(+)-decursin and its analogue have a variety of pharmacological activities. In the present study, the anti-inflammatory effect of a (S)-(+)-decursin derivative, (S)-(+)-3-(3,4-dihydroxy-phenyl)-acrylic acid 2,2-dimethyl-8-oxo-3,4-dihydro-2H,8H-pyrano [3,2-g]-chromen-3-yl-ester (Compound 6, C6), on in vitro and in vivo atopic dermatitis was investigated. C6 suppressed the secretion of IL-6, IL-8, and monocyte chemotactic protein-1 increase by the house dust mite extract in the eosinophilic leukemia cell line and THP-1 cells. C6 inhibited the production of TARC, IL-6, and IL-8 increase by IFN-γ and TNF-α in the human keratinocyte cell line. In the in vivo experiment, NC/Nga mice were sensitized to 2,4-dinitrochlorobenzene, and then C6 or dexamethasone (Dex) were orally and dorsally administered for three weeks. C6 treatment reduced the skin severity score compared with that of the control group. C6 inhibited the thickening of the epidermis and inflammatory cell infiltration into the dermis by evaluating the histological examination. The serum immunoglobulin E (IgE) level decreased in the C6-treated group compared with that of the control group. The inhibitory effect of C6 on IgE concentration was similar to that of Dex. The levels of IL-4, IL-5, IL-13, and eotaxin increased after treatment with concanavalin A in mouse splenocytes. The cytokine levels of the C6-treated group were lower than those of the control group. Taken together, C6 may attenuate atopic dermatitis-like lesions through its anti-inflammatory effect, such as inhibition of IgE and inflammatory cytokines, and it may be valuable as a therapeutic drug for the treatment of atopic dermatitis.