Why school is crucial to increase vaccination coverage for children: Evaluation of school vaccination check program in South Korea 2021-2022.

The School Vaccination Check Program (SVCP) is a public health measure that aims to achieve high levels of National Immunization Program (NIP) vaccination coverage for children by checking the completion of the vaccination schedule for students when they enter elementary or middle school. Due to the COVID-19 pandemic, the SVCP was stopped in 2020 and 2021, and restarted in June-August 2022. In this study, we examined and quantified the relationship with SVCP and the vaccination uptake by comparing the vaccination coverage of 2021 and 2022. Based on the standard schedule, the vaccination records of DTaP5, IPV4, MMR2 and IJEV4 were evaluated for elementary school students. The Tdap6, IJEV5 and HPV1 were evaluated for the students from middle school. Using a difference-in-difference study design and national level big data, the study compared vaccination coverage as of August 2021 and 2022. The study found that the SVCP was effective in increasing vaccination coverage for targeted vaccinations such as DTaP5, IPV4, MMR2 and IJEV4 for elementary school students, and Tdap6, IJEV5 for middle school students. However, the SVCP did not show a statistically significant effect on increasing vaccination coverage on HPV1 for middle school students. School can play an important role to improve vaccination coverage. Therefore, close collaboration with health and education authority is crucial to accomplish successful vaccination program reducing vaccine preventable disease outbreaks in schools.

Predicting graft failure in pediatric liver transplantation based on early biomarkers using machine learning models.

The early detection of graft failure in pediatric liver transplantation is crucial for appropriate intervention. Graft failure is associated with numerous perioperative risk factors. This study aimed to develop an individualized predictive model for 90-days graft failure in pediatric liver transplantation using machine learning methods. We conducted a single-center retrospective cohort study. A total of 87 liver transplantation cases performed in patients aged < 12 years at the Severance Hospital between January 2010 and September 2020 were included as data samples. Preoperative conditions of recipients and donors, intraoperative care, postoperative serial laboratory parameters, and events observed within seven days of surgery were collected as features. A least absolute shrinkage and selection operator (LASSO) -based method was used for feature selection to overcome the high dimensionality and collinearity of variables. Among 146 features, four variables were selected as the resultant features, namely, preoperative hepatic encephalopathy, sodium level at the end of surgery, hepatic artery thrombosis, and total bilirubin level on postoperative day 7. These features were selected from different times and represent distinct clinical aspects. The model with logistic regression demonstrated the best prediction performance among various machine learning methods tested (area under the receiver operating characteristic curve (AUROC) = 0.898 and area under the precision-recall curve (AUPR) = 0.882). The risk scoring system developed based on the logistic regression model showed an AUROC of 0.910 and an AUPR of 0.830. Together, the prediction of graft failure in pediatric liver transplantation using the proposed machine learning model exhibited superior discrimination power and, therefore, can provide valuable information to clinicians for their decision making during the postoperative management of the patients.

Perioperative Intravenous Lidocaine Infusion on Postoperative Recovery in Patients Undergoing Arthroscopic Rotator Cuff Repair Under General Anesthesia: A Randomized Controlled Trial.

OBJECTIVE: Arthroscopic rotator cuff repair (ARCR) is known to cause severe postoperative pain that may interfere with recovery. Intravenous (IV) lidocaine has analgesic, anti-inflammatory, and antihyperalgesic effects, and is being used in various types of surgeries. However, the effect of IV lidocaine in ARCR is not well-known. MATERIALS AND METHODS: Ninety patients undergoing ARCR were randomly allocated to receive IV lidocaine (1.5 mg/kg bolus of 1% lidocaine after anesthesia induction followed by a continuous infusion of 2 mg/kg/h up to 1 h after surgery) or an equal volume of saline. In both groups, an IV patient-controlled analgesia (PCA) device was used that contained fentanyl 10 µg/mL, infused at 1 mL/h with a 1 mL bolus dose. The primary outcome was fentanyl requirements given via IV PCA during the first 24 hours after surgery. Perioperative pain scores and functional recovery were assessed as secondary outcomes. RESULTS: The amount of fentanyl administered via IV PCA up to 24 hours after surgery was significantly lower in the lidocaine group compared with the control group (329 [256.2 to 428.3] vs. 394.5 [287.0 to 473.0], P=0.037). The number of PCA bolus attempts were lower in the lidocaine group without statistical significance. There were no differences in postoperative pain scores or functional shoulder scores between the 2 groups. DISCUSSION: IV lidocaine appears to be helpful in reducing opioid requirements during the acute postoperative period in patients undergoing ARCR. IV lidocaine may be a viable option as a component of multimodal analgesia in ARCR when regional analgesia is not possible.

Comparison of intraocular lens power formulas according to axial length after myopic corneal laser refractive surgery.

PURPOSE: To assess the predictive accuracy of 4 no-history intraocular lens (IOL) power formulas in eyes with prior myopic excimer laser surgery, classified in 4 groups according to their axial length (AL), and investigate the relationship between AL and predictive accuracy. SETTING: Seoul St. Mary's Hospital, Republic of Korea. DESIGN: Retrospective case series. METHODS: IOL power was calculated with the Barrett True-K, Haigis-L, Shammas-PL, and Triple-S formulas in 4 groups classified according to AL. Primary outcomes were the median absolute error (MedAE) and percentage of eyes with a prediction error (PE) within ±0.50 diopter (D). RESULTS: This study included 107 eyes of 107 patients. The Barrett True-K had the lowest MedAE when AL was <26.0 mm (0.30 D) and between 26.0 and 28.0 mm (0.54 D); in these subgroups, it had the highest percentages with a PE within ±0.50 D (71.4% and 46.2%). For AL between 28.0 and 30.0 mm, the Triple-S method showed the lowest MedAE (0.43 D) and highest percentage with a PE within ±0.50 D (58.3%). For AL ≥30.0 mm, the Shammas-PL formula produced the lowest MedAE (0.41 D) and highest percentage with a PE within ±0.50 D (58.3%). The Barrett True-K was the only formula with a correlation between AL and PE (r = -0.219/P = .023). CONCLUSIONS: The predictive accuracy of no-history IOL formulas depends on the AL. The Barrett True-K had the highest accuracy when AL was < 28.0 mm and the Triple-S when it ranged from 28.0 mm to 30.0 mm, whereas the Shammas-PL was more accurate when AL was ≥30.0 mm.

Ability of dynamic preload indices to predict fluid responsiveness in a high femoral-to-radial arterial pressure gradient: a retrospective study.

BACKGROUND: Dynamic preload indices may predict fluid responsiveness in end-stage liver disease. However, their usefulness in patients with altered vascular compliance is uncertain. This study is the first to evaluate whether dynamic indices can reliably predict fluid responsiveness in patients undergoing liver transplantation with a high femoral-to-radial arterial pressure gradient (PG). METHODS: Eighty liver transplant recipients were retrospectively categorized as having a normal (n = 56) or high (n = 24, difference in systolic pressure ≥ 10 mmHg and/or mean pressure ≥ 5 mmHg) femoral-to-radial arterial PG, measured immediately after radial and femoral arterial cannulation. The ability of dynamic preload indices (stroke volume variation, pulse pressure variation [PPV], pleth variability index) to predict fluid responsiveness was assessed before the surgery. Fluid replacement of 500 ml of crystalloid solution was performed over 15 min. Fluid responsiveness was defined as ≥ 15% increase in the stroke volume index. The area under the receiver-operating characteristic curve (AUC) indicated the prediction of fluid responsiveness. RESULTS: Fourteen patients in the normal, and eight in the high PG group were fluid responders. The AUCs for PPV in the normal, high PG groups and total patients were 0.702 (95% confidence interval [CI] 0.553-0.851, P = 0.008), 0.633 (95% CI 0.384-0.881, P = 0.295) and 0.667 (95% CI 0.537-0.798, P = 0.012), respectively. No other index predicted fluid responsiveness. CONCLUSIONS: PPV can be used as a dynamic index of fluid responsiveness in patients with end-stage liver disease but not in patients with altered vascular compliance.

Successful wire-guided fiberoptic nasotracheal intubation in a patient with hemifacial microsomia - A case report.

BACKGROUND: Patients with hemifacial microsomia may have a difficult airway due to the accompanying mandibular deformity. Fiberoptic bronchoscope-guided intubation is commonly used method for difficult airway management. However, awake fiberoptic nasotracheal intubation has several disadvantages, including difficulty in advancement of the endotracheal tube (ETT) due to the resistance between the ETT and bronchoscope. Wire-guided fiberoptic nasotracheal intubation may help to overcome the drawbacks of the conventional method. CASE: An 18-year-old man with hemifacial microsomia was scheduled for double-jaw surgery. In preoperative evaluation, he had severe retrognathia and expected difficult airway. We successfully performed wire-guided fiberoptic nasotracheal intubation combined with high-flow nasal cannula and deep sedation without any complications. CONCLUSIONS: A guidewire may be useful, in case of difficultly in advancing the ETT or if a smaller tube is required, while performing intubation with FOB in patients with difficult airways.

Sustained Vaccination Coverage during the Coronavirus Disease 2019 Epidemic in the Republic of Korea.

Amid the COVID-19 pandemic, vaccination coverage may decline due to limited accessibility to healthcare. We assessed the impact of the COVID-19 pandemic on vaccination coverage and the incidence of vaccine-preventable diseases (VPDs) in the Republic of Korea. National vaccination coverage of 10 essential vaccines administered to children between January-June 2019 and January-June 2020 was analyzed. The national incidence of selected VPDs was compared for the corresponding periods. During the COVID-19 outbreak, the vaccination rate in children aged 0-35 months in Korea did not decrease significantly, whereas the vaccination rate for children aged 4-6 years decreased by 1.4-1.9%. The overall incidence of VPDs decreased by 10-50% between 2019 and 2020, especially with varicella. Thus, the COVID-19 pandemic did not result in a decrease in vaccination coverage among Korean children, which prevented a surge in VPD incidence. Maintaining essential vaccination coverage without interruption is important during the response to the COVID-19 pandemic.

Effects of Anesthesia Techniques on Outcomes after Hip Fracture Surgery in Elderly Patients: A Prospective, Randomized, Controlled Trial.

The superiority of distinct anesthesia methods for geriatric hip fracture surgery remains unclear. We evaluated high mobility group box-1 (HMGB1) and interleukin-6 (IL-6) with three different anesthesia methods in elderly patients undergoing hip fracture surgery. Routine blood test findings, postoperative morbidity, and mortality were assessed as secondary outcome. In total, 176 patients were randomized into desflurane (n = 60), propofol (n = 58), or spinal groups (n = 58) that received desflurane-based balanced anesthesia, propofol-based total intravenous anesthesia (TIVA), or spinal anesthesia, respectively. The spinal group required less intraoperative vasopressors (p < 0.001) and fluids (p = 0.006). No significant differences in HMGB1 (pgroup×time = 0.863) or IL-6 (pgroup×time = 0.575) levels were noted at baseline, postoperative day (POD) 1, or POD2. Hemoglobin, albumin, creatinine, total lymphocyte count, potassium, troponin T, and C-reactive protein were comparable among groups at all time-points. No significant differences in postoperative hospital stay, intensive care unit (ICU) stay, and ventilator use among groups were observed. Postoperative pulmonary, cardiac, and neurologic complications; and in-hospital, 30-day, and 90-day mortality were not significantly different among groups (p = 0.974). In conclusion, HMGB1 and IL-6, and all secondary outcomes, were not significantly different between desflurane anesthesia, propofol TIVA, and spinal anesthesia.

Epidural bolus versus continuous epidural infusion analgesia on optic nerve sheath diameter in paediatric patients: A prospective, double-blind, randomised trial.

The use of programmed intermittent epidural bolus for postoperative analgesia may have greater analgesic efficacy than continuous epidural infusion. However, the rapid delivery speed used with an epidural bolus is more likely to increase intracranial pressure. We compared the effects of lumbar epidural bolus versus continuous infusion epidural analgesia on intracranial pressure in children using optic nerve sheath diameter as a marker. We randomly assigned 40 paediatric patients to bolus or infusion groups. Epidural analgesia (0.15% ropivacaine 0.3 ml·kg-1) was administered via bolus or infusion. Ultrasonography was used to measure the optic nerve sheath diameter before (T0), at 3 min (T1), 10 min (T2), and 70 min (T3) after starting the pump. There were statistically significant between-group differences in optic nerve sheath diameter over time (PGroup x Time = 0.045). From T0-T3, the area under the curve values were similar between the two groups. Although there were differences in the patterns of optic nerve sheath diameter change according to the delivery mode, the use of lumbar epidural bolus did not increase the risk of intracranial pressure increase over that of continuous infusion. Further research is needed to investigate intracranial pressure changes after continuous application of each delivery mode.

Use Of Regional Anesthesia For Lower Extremity Amputation May Reduce The Need For Perioperative Vasopressors: A Propensity Score-Matched Observational Study.

PURPOSE: Lower extremity amputation (LEA) is associated with a high risk of postoperative mortality. The effect of type of anesthesia on postoperative mortality has been studied in various surgeries. However, data for guiding the selection of optimal anesthesia for LEA are limited. This study aimed to determine the effect of anesthesia type on perioperative outcomes in patients with diabetes and/or peripheral vascular disease undergoing LEA. PATIENTS AND METHODS: We reviewed the medical records of patients who underwent LEA at our center between September 2007 and August 2017, who were grouped according to use of general anesthesia (GA) or regional anesthesia (RA). Primary outcomes were 30-day and 90-day mortality. Secondary outcomes were postoperative morbidity, intraoperative events, postoperative intensive care unit admission, and postoperative length of stay. Propensity score-matched cohort design was used to control for potentially confounding factors, including patient demographics, comorbidities, medications, and type of surgery. RESULTS: Five hundred and nineteen patients (75% male, mean age 65 years) were identified to have received GA (n=227) or RA (n=292) for above-knee amputation (1.5%), below-knee amputation (16%), or more minor amputation (82.5%). Before propensity score matching, there was an association of GA with coronary artery disease (44% [GA] vs 34.5% [RA], p=0.028), peripheral arterial disease (73.1% vs 60.2%, p=0.002), and preoperative treatment with aspirin and clopidogrel (68.7% vs 55.1%, p=0.001; 63% vs 41.8%, p<0.001, respectively). Propensity score matching produced a cohort of 342 patients equally divided between GA and RA. There was no significant between-group difference in 30-day (3.5% vs 2.9%, p=0.737) or 90-day (6.4% vs 4.6%, p=0.474) mortality or postoperative morbidity. However, postoperative ICU admission (14.6% vs 7%, p=0.032), intraoperative hypotension (61.4% vs 14.6%, p<0.001), and vasopressor use (52% vs 14%, p<0.001) were more common with GA than with RA. CONCLUSION: Type of anesthesia did not significantly affect mortality or morbidity after LEA. However, intraoperative hypotension, vasopressor use, and postoperative ICU admission rates were lower with RA.

Accuracy and Efficacy of Impedance Cardiography as a Non-Invasive Cardiac Function Monitor.

PURPOSE: The most common method of monitoring cardiac output (CO) is thermodilution using pulmonary artery catheter (PAC), but this method is associated with complications. Impedance cardiography (ICG) is a non-invasive CO monitoring technique. This study compared the accuracy and efficacy of ICG as a non-invasive cardiac function monitoring technique to those of thermodilution and arterial pressure contour. MATERIALS AND METHODS: Sixteen patients undergoing liver transplantation were included. Cardiac index (CI) was measured by thermodilution using PAC, arterial waveform analysis, and ICG simultaneously in each patient. Statistical analysis was performed using intraclass correlation coefficient (ICC) and Bland-Altman analysis to assess the degree of agreement. RESULTS: The difference by thermodilution and ICG was 1.13 L/min/m², and the limits of agreement were -0.93 and 3.20 L/min/m². The difference by thermodilution and arterial pressure contour was 0.62 L/min/m², and the limits of agreement were -1.43 and 2.67 L/min/m². The difference by arterial pressure contour and ICG was 0.50 L/min/m², and the limits of agreement were -1.32 and 2.32 L/min/m². All three percentage errors exceeded the 30% limit of acceptance. Substantial agreement was observed between CI of thermodilution with PAC and ICG at preanhepatic and anhepatic phases, as well as between CI of thermodilution and arterial waveform analysis at preanhepatic phase. Others showed moderate agreement. CONCLUSION: Although neither method was clinically equivalent to thermodilution, ICG showed more substantial correlation with thermodilution method than with arterial waveform analysis. As a non-invasive cardiac function monitor, ICG would likely require further studies in other settings.

Predictors of the analgesic efficacy of pulsed radiofrequency treatment in patients with chronic lumbosacral radicular pain: a retrospective observational study.

BACKGROUND: Pulsed radiofrequency (RF) targeting the adjacent dorsal root ganglion (DRG) is one treatment option for lumbosacral radicular pain. However, the analgesic efficacy of this procedure is not always guaranteed. The aim of this retrospective study was to identify the predictors of the analgesic efficacy of pulsed DRG RF treatment in patients with chronic lumbosacral radicular pain. METHODS: Patients who underwent pulsed DRG RF treatment from 2006 to 2017 at our clinic were enrolled. Positive response was defined as a ≥50% reduction in pain score from baseline at day 30. Patient demographics, pain-related factors, and clinical factors were evaluated using logistic regression analysis to identify the predictors of a positive response to the treatment. RESULTS: A total of 60 patients satisfied the study protocol requirements. Twenty-eight patients (46.7%) had a positive outcome. Multivariate logistic regression analysis revealed that the absence of comorbid musculoskeletal pain (OR=0.518, 95% CI=0.029-0.858, P=0.033) and positive response to previous epidural steroid injection (OR=3.269, 95% CI=1.046-10.215, P=0.042) were independent predictors of the analgesic efficacy of pulsed DRG RF treatment. CONCLUSION: Comorbid musculoskeletal pain and previous epidural injection response appear to affect the outcome of pulsed DRG RF treatment in patients with chronic lumbosacral radicular pain.

Comparison of Incidences of Intravascular Injection between Medial and Lateral Side Approaches during Traditional S1 Transforaminal Epidural Steroid Injection.

Purpose. Intravascular injection rates are higher during traditional S1 transforaminal epidural steroid injection (TFESI) compared with lumbar transforaminal injection. We compared the incidences of intravascular injection between the medial and lateral approaches to the S1 foramen during S1 TFESI. Materials and Methods. A total of 139 patients underwent one or more TFESIs (170 total injections). The patients received S1 TFESI by either medial or lateral side of S1 foramen under fluoroscopic anteroposterior view using digital subtraction method. The intravascular injection rates, epidural spread patterns, and contrast volumes required to reach the superior aspect of the L5-S1 intervertebral disc (SIVD) were compared between groups. Results. Intravascular injection rates during S1 TFESI were significantly lower in the medial approach compared with the lateral approach patients (4.9% versus 38.6%, resp., P < 0.001). The medial approach group had more epidural spread to the L5-S1 SIVD than the lateral group (82.1% versus 58.8%, resp.); lower contrast volume amounts were required to extend the L5-S1 SIVD (1.46 ± 0.48 versus 1.90 ± 0.62, resp.). Conclusion. During S1 TFESI, approaching the needle towards the medial part of the S1 foramen may reduce intravascular injection risk.

Effects of remifentanil and remifentanil-alfentanil administration on emergence agitation after brief ophthalmic surgery in children.

BACKGROUND: Sevoflurane is commonly usedin pediatric anesthesia due to its non-irritating airway properties, and rapid induction and emergence. However, it is associated with emergence agitation (EA) in children. EA may cause injury to the child or damage to the surgical site and is a cause of stress to both caregivers and families. The efficacy of remifentanil and additional alfentanil on EA in the pediatric patients underwent ophthalmic surgery with sevofluraneanesthesiawas not well evaluated to date. This study was designed to compare the effects of remifentanil and remifentanil plus alfentanil on EA in children undergoing ophthalmic surgery with sevofluraneanesthesia. METHODS: Children (aged 3-9 years) undergoing ophthalmic surgery undersevoflurane anesthesia were randomly assigned to group S (sevoflurane alone), group R (sevofluraneandremifentanil infusion, 0.1 µg/kg/min), or group RA (sevoflurane withremifentanil infusion and intravenous injection of alfentanil 5 µg/kg 10 min before the end of surgery). Mean arterial pressure (MAP), heart rate (HR), and sevoflurane concentration were checked every 15 min after induction of anesthesia. The incidence of EA, time to extubation from discontinuation of sevoflurane inhalation, and time to discharge from the postanesthesia care unit was assessed. RESULTS: The incidence of EA was significantly lower in groups R (32 %, 11/34; P = 0.01) and RA (31 %, 11/35; P = 0.008) than group S (64 %, 21/33). The time to extubation was prolonged in group RA (11.2 ± 2.3 min; P = 0.004 and P = 0.016) compared with groups S (9.2 ± 2.3 min) andR (9.5 ± 2.4 min). MAP and HR were similar in all three groups, apart from a reduction in HR at 45 min in groups R and RA. However, the sevoflurane concentration was lower in groups R and RA than group S (P < 0.001). CONCLUSIONS: The administration of remifentanil to children undergoing ophthalmic surgery undersevoflurane anesthesia reduced the incidence of EA without clinically significant hemodynamic changes. However, the addition of alfentanil(5 µg/kg)10 min before the end of surgery provided no additional benefit compared withremifentanil alone. CLINICAL TRIAL NUMBER: NCT02486926 , June.29.2015.

Cardiac arrest due to intracranial hypotension following pseudohypoxic brain swelling induced by negative suction drainage in a cranioplasty patient: a case report.

Pseudohypoxic brain swelling (PHBS) is known to be an uncommon event that may occur during and following an uneventful brain surgery, when negative suction drainage is used. The cerebrospinal fluid loss related to suction drainage can evoke intracranial hypotension that progress to PHBS. The main presentations of PHBS are sudden unexpected circulatory collapses, such as severe bradycardia, hypotension, cardiac arrest, consciousness deterioration and diffuse brain swelling as seen with brain computerized tomography (CT). We present a stuporous 22-year-old patient who underwent cranioplasty under general anesthesia. The entire course of the general anesthesia and operation progressed favorably. However, the time of scalp suture completion, sudden bradycardia and hypotension occurred, followed by cardiac arrest immediately after initiation of subgaleal and epidural suction drainage. After successful resuscitation, the comatose patient was transferred to the neurosurgical intensive care unit and PHBS was confirmed using brain CT.

Toxicity of colloidal silica nanoparticles administered orally for 90 days in rats.

This study was undertaken to investigate the potential toxicity and establish the no observed adverse effect level (NOAEL) and target organ(s) of negatively charged colloidal silica particles of different sizes, ie, SiO2 (EN20(-)) (20 nm) or SiO2 (EN100(-)) 2(100 nm), administered by gavage in Sprague-Dawley rats. After verification of the physicochemical properties of the SiO2 particles to be tested, a preliminary dose range-finding study and 90-day repeated dose study were conducted according to the Organisation for Economic Cooperation and Development test guideline. Based on the results of the 14-day dose range-finding study, a high dose was determined to be 2,000 mg/kg, and middle and low doses were set at 1,000 and 500 mg/kg, respectively. In the 90-day toxicity study, there were no animal deaths in relation to administration of SiO2 particles of either size. In addition, no treatment-related clinical changes or histopathological findings were observed in any of the experimental groups. Moreover, no difference in toxic effects from chronic exposure to SiO2 (EN20(-))(20 nm) or SiO2 (EN100(-)) (100 nm) was observed. The results of this study indicate that the NOAEL for SiO2 (EN20(-)) and SiO2 (EN100(-)) would most likely be 2,000 mg/kg, and no target organ was identified in rats of either sex.

A 90-day study of sub-chronic oral toxicity of 20 nm positively charged zinc oxide nanoparticles in Sprague Dawley rats.

PURPOSE: The study reported here was conducted to determine the systemic oral toxicity and to find the no-observed-adverse-effect level of 20 nm positively charged zinc oxide (ZnO(SM20(+))) nanoparticles in Sprague Dawley rats for 90 days. METHODS: For the 90-day toxicity study, the high dose was set as 500 mg per kg of body weight (mg/kg) and the middle and low dose were set to 250 mg/kg and 125 mg/kg, respectively. The rats were held for a 14-day recovery period after the last administration, to observe for the persistence or reduction of any toxic effects. A distributional study was also carried out for the systemic distribution of ZnO(SM20(+)) NPs. RESULTS: No rats died during the test period. There were no significant clinical changes due to the test article during the experimental period in functional assessment, body weight, food and water consumption, ophthalmological testing, urine analysis, necropsy findings, or organ weights, but salivation was observed immediately after administration in both sexes. The total red blood cell count was increased, and hematocrit, albumin, mean cell volume, mean cell hemoglobin, and mean cell hemoglobin concentration were decreased significantly compared with control in both 500 mg/kg groups. Total protein and albumin levels were decreased significantly in both sexes in the 250 and 500 mg/kg groups. Histopathological studies revealed acinar cell apoptosis in the pancreas, inflammation and edema in stomach mucosa, and retinal atrophy of the eye in the 500 mg/kg group. CONCLUSION: There were significant parameter changes in terms of anemia in the hematological and blood chemical analyses in the 250 and 500 mg/kg groups. The significant toxic change was observed to be below 125 mg/kg, so the no-observed-adverse-effect level was not determined, but the lowest-observed-adverse-effect level was considered to be 125 mg/kg in both sexes and the target organs were found to be the pancreas, eye, and stomach.

Calcium/Calmodulin-Dependent Protein Kinase is Involved in the Release of High Mobility Group Box 1 Via the Interferon-ß Signaling Pathway.

Previously, we have reported that high mobility group box 1 (HMGB1), a proinflammatory mediator in sepsis, is released via the IFN-ß-mediated JAK/STAT pathway. However, detailed mechanisms are still unclear. In this study, we dissected upstream signaling pathways of HMGB1 release using various molecular biology methods. Here, we found that calcium/calmodulin-dependent protein kinase (CaM kinase, CaMK) is involved in HMGB1 release by regulating IFN-ß production. CaMK inhibitor, STO609, treatment inhibits LPS-induced IFN-ß production, which is correlated with the phosphorylation of interferon regulatory factor 3 (IRF3). Additionally, we show that CaMK-I plays a major role in IFN-ß production although other CaMK members also seem to contribute to this event. Furthermore, the CaMK inhibitor treatment reduced IFN-ß production in a murine endotoxemia. Our results suggest CaMKs contribute to HMGB1 release by enhancing IFN-ß production in sepsis.

Co-administration of live attenuated Salmonella enterica serovar Typhimurium expressing swine interleukin-18 and interferon-α provides enhanced Th1-biased protective immunity against inactivated vaccine of pseudorabies virus.

The co-administration of two or more cytokines may generate additive or synergistic effects for controlling infectious diseases. However, the practical use of cytokine combinations for the modulation of immune responses against inactivated vaccine has not been demonstrated in livestock yet, primarily due to protein stability, production, and costs associated with mass administration. In light of the current situation, we evaluated the immunomodulatory functions of the combined administration of swine interleukin-18 (swIL-18) and interferon-α (swIFN-α) against an inactivated PrV vaccine using attenuated Salmonella enterica serovar Typhimurium as a cytokine delivery system. Co-administration of S. enterica serovar Typhimurium expressing swIL-18 and swIFN-α produced enhanced Th1-biased humoral and cellular immune responses against the inactivated PrV vaccine, when compared to single administration of S. enterica serovar Typhimurium expressing either swIL-18 or swIFN-α. Also, enhanced immune responses in co-administered piglets occurred rapidly after virulent PrV challenge, and piglets that received co-administration of S. enterica serovar Typhimurium expressing swIL-18 and swIFN-α displayed a greater alleviation of clinical severity following the virulent PrV challenge, as determined by clinical scores and cumulative daily weight gain. Furthermore, this enhancement was confirmed by reduced nasal shedding of PrV following viral challenge. Therefore, these results suggest that oral co-administration of S. enterica serovar Typhimurium expressing swIL-18 and swIFN-α provide enhanced Th1-biased immunity against inactivated PrV vaccine to alleviate clinical signs caused by PrV challenge.

Oral administration of Salmonella enterica serovar Typhimurium expressing swine interleukin-18 induces Th1-biased protective immunity against inactivated vaccine of pseudorabies virus.

Enhancing and/or modulating innate and adaptive immunity by cytokines appears to be greatly useful to provide effective protective immunity against infectious diseases. However, an effective delivery system for mass administration in livestock industry is needed because of limitations such as cost, labor, time, and protein stability. Here the immunomodulatory functions of swine interleukine-18 (swIL-18), known as IFN-γ-inducing factor (IGIF), were evaluated in a vaccination model of pseudorabies virus (PrV) using attenuated Salmonella enterica serovar Typhimurium as the oral delivery system. The oral administration of S. enterica serovar Typhimurium expressing swIL-18 prior to vaccination with inactivated PrV vaccine induced enhanced levels of serum PrV-specific IgG and its IgG2 isotype, compared to administration of S. enterica serovar Typhimurium harboring the empty vector. Furthermore, S. enterica serovar Typhimurium expressing swIL-18 mounted Th1-biased cellular immune responses against PrV antigen, as evaluated by the production of IFN-γ and IL-4 from peripheral blood mononuclear cells of piglets. Subsequently, Th1-biased immunity induced by S. enterica serovar Typhimurium expressing swIL-18 showed rapid response and rendered piglets displayed more alleviated clinical signs following the virulent PrV challenge. Also, this alleviation of clinical signs was further confirmed by the reduction of nasal excretion of PrV after challenge. The present study demonstrates the extended use of immunomodulatory functions of swIL-18 orally delivered by attenuated S. enterica serovar Typhimurium.