Evaluation of acute, 28-day, 13-week repeated dose oral toxicity and genotoxicity of a herbal extract (HemoHIM G) from Angelica sinensis, Ligusticum chuanxiong, and Peaonia lactiflora.

HemoHIM G is a functional food ingredient composed of a triple herbal combination of Angelica sinensis, Ligusticum chuanxiong, and Paeonia lactiflora, to improve impaired immune function. Considering the pharmacological benefits of its constituent herbal components, HemoHIM G is anticipated to have various health benefits; however, its toxicity has not been thoroughly evaluated. Here, we conducted a comprehensive study to assess the safety of HemoHIM G in terms of acute oral toxicity, 13-week repeat-dose toxicity, and genotoxicity. In the oral acute toxicity study, Sprague-Dawley rats were orally administered a single dose of HemoHIM G at 5000 mg/kg/day, the limit dose for the acute study. No abnormal findings or adverse effects were observed in this study, as confirmed by gross pathology. A 13-week repeated-dose toxicity study was conducted with HemoHIM G at doses of 1250, 2500, and 5000 mg/kg/day to examine the subchronic toxicity in both male and female rats after 28 days of dose-range finding study. No test substance-related clinical signs or mortality was observed at any of the tested doses. Gross pathology, hematology, blood chemistry, and histopathology were within normal ranges, further supporting the safety of HemoHIM G. Therefore, the NOAEL of HemoHIM G was considered to be at 5000 mg/kg/day for both sexes of rats. Bacterial reverse mutation tests, a chromosome aberration test in human peripheral blood lymphocytes, and a mouse micronuclei test were conducted to identify the potential genotoxicity of HemoHIM G. HemoHIM G is non-mutagenic and non-clastogenic. Collectively, these findings provide valuable evidence for the safe use of HemoHIM G as a functional food ingredient.

Critical diagnostic and cancer stem cell markers in neoplastic cells from canine primary and xenografted pulmonary adenocarcinoma.

It is challenging to diagnose metastatic tumors whose cellular morphology is different from the primary. We characterized canine primary pulmonary adenocarcinoma (PAC) and its xenografted tumors by histological and immunohistochemical analyses for critical diagnostic and cancer stem cell (CSC) markers. To generate a tumor xenograft model, we subsequently transplanted the tissue pieces from the PAC into athymic nude mice. Immunohistochemical examination was performed for diagnostic (TTF-1, Napsin A, and SP-A) and CSC markers (CD44 and CD133). The use of CSC markers together with diagnostic markers can improve the detection and diagnosis of canine primary and metastatic adenocarcinomas.

Application of alginate microbeads as a carrier of bone morphogenetic protein-2 for bone regeneration.

Bone morphogenetic protein-2 (BMP-2) is commonly used to enhance bone regeneration. The potential of BMP-2 for bone regeneration varies according to the concentration and release kinetics on the implanted site. Therefore, it is important to determine appropriate carriers of BMP-2. However, no optimal delivery vehicles have been identified. In the present study, we used alginate microbeads as a delivery vehicle for BMP-2. Alginate microbeads can be implanted onto the disease site through surgery or injection. The objective of this study was to evaluate that the osteoinductive properties of BMP-2 are effective in alginate microbeads as a carrier. In this study, the release kinetics of BMP-2 in alginate microbeads was evaluated using an enzyme-linked immunosorbent assay. BMP-2 released from alginate microbeads induced high alkaline phosphatase activity in canine adipose tissue-derived mesenchymal stem cells. Injection of alginate microbeads with BMP-2 into mouse subcutaneous tissue, as well as surgical implantation into the 5-mm circular calvarial defects in rats, was conducted and the results showed extensive new bone formation. In conclusion, alginate microbeads can be utilized as an effective BMP-2 delivery vehicle for use in orthopedic surgery and as an injectable vehicle for a minimally invasive therapy. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 107B: 286-294, 2019.

Exogenous recombinant human thioredoxin-1 prevents acetaminophen-induced liver injury by scavenging oxidative stressors, restoring the thioredoxin-1 system and inhibiting receptor interacting protein-3 overexpression.

Thioredoxin-1 (Trx-1) is a potent therapeutic agent against a variety of diseases because of its actions as an antioxidant and regulator of apoptosis. N-acetyl-p-aminophenol (APAP), commonly known as acetaminophen, generates excessive oxidative stress and triggers hepatocyte cell death, exemplified by regulated necrosis. In the present study, we investigated whether APAP-induced liver injury in a mouse model is associated with "necroptosis," and if pretreatment with recombinant Trx-1 prevents the hepatic injury caused by APAP overdose. We also explored the mechanism underlying the preventive action of Trx-1 against APAP-induced hepatic injury. In a prevention study, C3H/he mice received different doses (0, 10, 50 or 100 mg kg-1 body weight) of recombinant human Trx-1 intraperitoneally, followed by a single oral dose of 300 mg kg-1 of APAP. In this experimental paradigm, liver injury and lethality were markedly decreased in rhTrx-1-pretreated mice. In survival experiments, mice received rhTrx-1 followed by oral administration of a lethal dose of APAP. APAP overdose caused a series of liver toxicity-associated events, beginning with overexpression of c-fos, excessive production of reactive oxygen species and reactive nitrogen species (RNS) and leading to decreased endogenous Trx-1 expression and activation of JNK signaling pathways. Pretreatment with rhTrx-1 inhibited all of these toxicological manifestations of APAP. In addition, rhTrx-1 significantly reduced the expression of RIP-3, a critical necrosome component. Taken together, our findings indicate that rhTrx-1 prevents APAP-induced liver injury through multiple action mechanisms, including scavenging reactive oxygen species and reactive nitrogen species, restoring endogenous Trx-1 levels and inhibiting RIP-3 overexpression.

Identification and characterization of avian hepatitis E virus genotype 2 from chickens with hepatitis-splenomegaly syndrome in Korea.

A new avian hepatitis E virus (HEV) GI-B was identified in broiler breeders with hematomas, liver rupture, and splenomegaly, along with excessive abdominal fat, in Korea. Previously, genotype 1 had been identified in avian HEV strains in Korea. Complete sequence analyses revealed that the new avian HEV clustered in genotype 2, which has been identified in the USA and Spain; the GI-B isolate was closely related to the USA prototype avian HEV isolated from a chicken with hepatitis-splenomegaly syndrome. Although some HEV genotypes show a geographical distribution pattern, the discovery of genotype 2 in addition to genotype 1 in Korea suggests that the geographical grouping might be reconsidered. These findings have important implications for understanding the global epidemiology and spread of avian HEV.

Cysticercus fasciolaris infection in wild rats (Rattus norvegicus) in Korea and formation of cysts by remodeling of collagen fibers.

Cysticercus fasciolaris, the larval form of Taenia taeniaeformis, is commonly encountered in rodents. In our study, 287 wild rats (Rattus norvegicus) in South Korea were examined in 2010 and 2011. Of 287 rats, 97 (33.8%) were infected with C. fasciolaris A strong positive correlation was found between the host body weight and prevalence in both sexes, regardless of the year of collection. The liver was the most common habitat of the parasite, and the lung was the most frequent ectopic region, followed by mesentery, pleura, abdominal wall, and kidney. The lesions of the affected organs were generally characterized by well-developed cysts, each containing a larva. However, the cysts within kidney and abdominal wall were poorly organized, filled with abscess, and lacked larvae. Collagen types I and III, but not type IV, played significant roles in constructing the cysts at differential stages, addressed by immunohistochemistry. During cyst wall development, both collagen types contributed equally to cyst formation at the early stage, whereas collagen type I was the major component at the late stage (p < 0.05). In early-stage cysts, distribution of collagens was interestingly differential depending on the development stage, as collagen type I was localized in the outer layer and type III was located in the inner layer. Our results suggest that an appropriate remodeling process of collagen fibers is necessary for C. fasciolaris to build the well-conditioned cysts in the target organs for survival.

Inhalation of Talc Induces Infiltration of Macrophages and Upregulation of Manganese Superoxide Dismutase in Rats.

Talc is a mineral that is widely used in cosmetic products, antiseptics, paints, and rubber manufacturing. Although the toxicological effects of talc have been studied extensively, until now no detailed inhalation study of talc focusing on oxidative stress has been done. This repeated 4 weeks whole-body inhalation toxicity study of talc involved Sprague-Dawley rats. Male and female groups of rats were exposed to inhaled talc at 0, 5, 50, and 100 mg/m(3) for 6 hours daily, 5 days/week for 4 weeks. The objective was to identify the 4-week inhalation toxicity of talc and investigate antioxidant activity after exposure to talc. There were no treatment-related symptoms or mortality in rats treated with talc. Glucose (GLU) was decreased significantly in male rats exposed to 50 and 100 mg/m(3) of talc. Histopathological examination revealed infiltration of macrophages on the alveolar walls and spaces near the terminal and respiratory bronchioles. In male and female rats exposed to 100 mg/m(3) talc, expression of superoxide dismutase 2, a typical biological indicator of oxidative damage, was significantly increased. Thus, inhalation of talc induces macrophage aggregations and oxidative damage in the lung.

Construction of an infectious cDNA clone of genotype 1 avian hepatitis E virus: characterization of its pathogenicity in broiler breeders and demonstration of its utility in studying the role of the hypervariable region in virus replication.

A full-length infectious cDNA clone of the genotype 1 Korean avian hepatitis E virus (avian HEV) (pT11-aHEV-K) was constructed and its infectivity and pathogenicity were investigated in leghorn male hepatoma (LMH) chicken cells and broiler breeders. We demonstrated that capped RNA transcripts from the pT11-aHEV-K clone were translation competent when transfected into LMH cells and infectious when injected intrahepatically into the livers of chickens. Gross and microscopic pathological lesions underpinned the avian HEV infection and helped characterize its pathogenicity in broiler breeder chickens. The avian HEV genome contains a hypervariable region (HVR) in ORF1. To demonstrate the utility of the avian HEV infectious clone, several mutants with various deletions in and beyond the known HVR were derived from the pT11-aHEV-K clone. The HVR-deletion mutants were replication competent in LMH cells, although the deletion mutants extending beyond the known HVR were non-viable. By using the pT11-aHEV-K infectious clone as the backbone, an avian HEV luciferase reporter replicon and HVR-deletion mutant replicons were also generated. The luciferase assay results of the reporter replicon and its mutants support the data obtained from the infectious clone and its derived mutants. To further determine the effect of HVR deletion on virus replication, the capped RNA transcripts from the wild-type pT11-aHEV-K clone and its mutants were injected intrahepatically into chickens. The HVR-deletion mutants that were translation competent in LMH cells displayed in chickens an attenuation phenotype of avian HEV infectivity, suggesting that the avian HEV HVR is important in modulating the virus infectivity and pathogenicity.

Preoperative erythropoietin administration in patients with prostate cancer undergoing radical prostatectomy without transfusion.

PURPOSE: In this study, we administered erythropoietin preoperatively to patients who underwent open radical prostatectomy without transfusion to increase their hemoglobin levels and investigated the efficacy of this procedure. MATERIALS AND METHODS: We evaluated 62 patients who underwent open radical prostatectomy performed by the same surgeon between June 2005 and January 2011. The 22 patients who refused transfusion were assigned to group 1; the patients who accepted transfusion were assigned to group 2. Before surgery, we administered erythropoietin beta to group 1 patients whose hemoglobin levels were <12 g/dL and retrospectively compared the clinical data of the two groups. We used the t-test and the chi-square test for statistical analysis. RESULTS: Mean preoperative hemoglobin levels in group 1 after erythropoietin administration (14.5 g/dL) were significantly higher than those in group 2 (13.59 g/dL, p=0.003). Moreover, the difference in the mean hemoglobin levels before and after surgery for group 1 patients (3.55 g/dL) significantly exceeded that for group 2 patients (2.08 g/dL, p=0.000). Additional analysis revealed no statistically significant differences in perioperative complications between the groups. CONCLUSIONS: Preoperative erythropoietin administration increased the safety margin of hemoglobin levels, and this strategy worked sufficiently well in our experience.

Inhalation exposure to chloramine T induces DNA damage and inflammation in lung of Sprague-Dawley rats.

Chloramine T has been widely used as a disinfectant in many areas such as kitchens, laboratories and hospitals. It has been also used as a biocide in air fresheners and deodorants which are consumer products; however, little is known about its toxic effects by inhalation route. This study was performed to identify the subacute inhalation toxicity of chloramine T under whole-body inhalation exposure conditions. Male and female groups of rats were exposed to chloramine T at concentrations of 0.2, 0.9 and 4.0 mg/m³ for 6 hr/day, 5 days/week during 4 weeks. After 28-day repeated inhalation of chloramine T, there were dose-dependently significant DNA damage in the rat tissues evaluated and inflammation was histopathologically noted around the terminal airways of the lung in both genders. As a result of the expression of three types of antioxidant enzymes (SOD-2, GPx-1, PRX-1) in rat's lung after exposure, there was no significant change of all antioxidant enzymes in the male and female rats. The results showed that no observed adverse effect level (NOAEL) was 0.2 mg/m³ in male rats and 0.9 mg/m³ in female rats under the present experimental condition.

Uterine leiomyosarcoma in a wild rat (Rattus norvegicus): usefulness of Ki-67 labeling index for diagnosis.

Uterine smooth muscle tumor is very rare in laboratory rats and, there has been no report in the wild rodents. Among a total of 400 wild rats captured in Gyeonggi, Gangwon, and Chungbuk provinces of Korea in 2007, 2010, and 2011, we found a uterine spindle cell tumor, diagnosed as smooth muscle cell origin based on differential features of histology and immunohistochemistry. Its incidence was very low, like in the laboratory rats, as under 0.5% for female. Considering generally applied histological and cellular criteria, this case was difficult in differential diagnosis between benign and malignant. Ki-67 labeling index was therefore further investigated, and it ranged from 26.4 to 37.6% in the 10 different areas, representing an average of 32.9±0.05%. The Ki-67 labeling index of neoplastic cells near the necrotic area was recorded as 83.5%. According to such high Ki-67 labeling index, it was more likely a malignant leiomyosarcoma, assenting to the previous proposal that Ki-67 labeling index is a significant criterion to differentiate between malignant and benign in the smooth muscle tumors.

Primary adenocarcinoma of the rete testis with preceding detection of unilateral hydronephrosis.

Primary adenocarcinoma of the rete testis is a rare malignant testicular tumor with a poor prognosis. Here we report the case of a 54-year-old man with right hydronephrosis that was detected before the diagnosis of the primary testicular lesion. During the evaluation of the right hydronephrosis by use of abdominopelvic computed tomography, a painless, hard, solid lesion was found on the right testis. The patient underwent radical orchiectomy, and the pathologic examination revealed an adenocarcinoma of the rete testis. Multiple metastases were present at the time of diagnosis. The patient received combined chemotherapy after the surgery but lived only 8 months after the initial diagnosis.

Aluminum Nanoparticles Induce ERK and p38MAPK Activation in Rat Brain.

Aluminum nanoparticles (Al-NPs) are one of the most widely used nanomaterial in cosmetics and medical materials. For this reason, Al-NP exposure is very likely to occur via inhalation in the environment and the workplace. Nevertheless, little is known about the mechanism of Al-NP neurotoxicity via inhalation exposure. In this study, we investigated the effect AL-NPs on the brain. Rats were exposed to Al-NPs by nasal instillation at 1 mg/kg body weight (low exposure group), 20 mg/kg body weight (moderate exposure group), and 40 mg/kg body weight (high exposure group), for a total of 3 times, with a 24-hr interval after each exposure. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated that the presence of aluminum was increased in a dose-dependent manner in the olfactory bulb (OFB) and the brain. In microarray analysis, the regulation of mitogen-activated protein kinases (MAPK) activity (GO: 0043405), including Ptprc, P2rx7, Map2k4, Trib3, Trib1, and Fgd4 was significantly over-expressed in the treated mice than in the controls (p = 0.0027). Moreover, Al-NPs induced the activation of ERK1 and p38 MAPK protein expression in the brain, but did not alter the protein expression of JNK, when compared to the control. These data demonstrate that the nasal exposure of Al-NPs can permeate the brain via the olfactory bulb and modulate the gene and protein expression of MAPK and its activity.

Optimum conductive fabric sensor sites for evaluating the status of knee joint movements using bio-impedance.

BACKGROUND: There have been many studies that utilize the bio-impedance measurement method to analyze the movements of the upper and lower limbs. A fixed electrical current flows into the limbs through four standard disposable electrodes in this method. The current flows in the muscles and blood vessels, which have relatively low resistivity levels in the human body. This method is used to measure bio-impedance changes following volume changes of muscles and blood vessels around a knee joint. The result of the bio-impedance changes is used to evaluate the movements. However, the method using the standard disposable electrodes has a restriction related to its low bio-impedance changes: the standard disposable electrodes are only able to measure bio-impedance from a limited part of a muscle. Moreover, it is impossible to use continuously, as the electrodes are designed to be disposable. This paper describes a conductive fabric sensor (CFS) using a bio-impedance measurement method and determines the optimum configuration of the sensor for estimating knee joint movements. METHODS: The upper side of subjects' lower limbs was divided into two areas and the lower side of subjects' lower limbs was divided into three areas. The spots were matched and 6 pairs were selected. Subjects were composed of 15 males (age: 30.7 ± 5.3, weight: 69.8 ± 4.2 kg, and height: 173.5 ± 2.8 cm) with no known problems with their knee joints. Bio-impedance changes according to knee joint flexion/extension assessments were calculated and compared with bio-impedance changes by an ankle joint flexion/extension test (SNR I) and a hip joint flexion/extension test (SNR II). RESULTS: The bio-impedance changes of the knee joint flexion/extension assessment were 35.4 ± 20.0 Ω on the (1, 5) pair. SNR I was 3.8 ± 8.4 and SNR II was 6.6 ± 7.9 on the (1, 5) pair. CONCLUSIONS: The optimum conductive fabric sensor configuration for evaluating knee joint movements were represented by the (1, 5) pair.

Kinematic analysis of the lumbar spine by digital videofluoroscopy in 18 asymptomatic subjects and 9 patients with herniated nucleus pulposus.

OBJECTIVES: The purpose of this study was to use digital videofluoroscopy to identify motion patterns of the lumbar spine during coronal movement in asymptomatic (normal) subjects and patients with herniated nucleus pulposus (HNP). METHODS: Videofluoroscopic lumbar coronal motion was recorded in 18 asymptomatic volunteers and 9 patients with HNP. Measurements were made while patients bent laterally and rotated toward the right and left from a sitting position and then returned to their original position. Direction and degree of extension in the coronal plane at each motion segment and sacral descent were measured. Through the motion analysis software, the coupled pattern with lateral bending and rotation was analyzed in the asymptomatic subjects and patients with HNP. RESULTS: Lateral flexion movement was coupled with contralateral extension and ipsilateral sacral descent but with a different rotation pattern. Rotation movement was coupled with ipsilateral extension, ipsilateral sacral descent, and ipsilateral spinous process rotation. Patients with HNP and asymptomatic subjects had similar coupled patterns but differences in amount of motion. CONCLUSIONS: Digital videofluoroscopy showed coupled patterns during the lateral bending and rotation movements.

Midterm results of primary total hip arthroplasty using highly cross-linked polyethylene: minimum 7-year follow-up study.

The purpose of this study was to investigate the results of 113 total hip arthroplasties in 109 patients using highly cross-linked polyethylene (HXLPE) after midterm (minimum 7 years) follow-up retrospectively. The mean age at the time of operation was 57 years. Preoperative diagnosis was osteonecrosis in 81 hips and other diagnosis in 32 hips. There was no component loosening. Acetabular osteolysis was found in 12 hips (10.6 %). Mean linear HXLPE wear rate was 0.031 ± 0.012 mm/y. We analyzed the relationship between HXLPE wear rate and several variables influencing HXLPE wear. Only the cup position was related with wear rate of HXLPE significantly (P < .05). The results of total hip arthroplasties using HXLPE showed excellent results with decreased wear rate and low incidence of osteolysis after midterm follow-up.

Simple in situ decompression for idiopathic cubital tunnel syndrome using minimal skin incision.

Cubital tunnel syndrome is one of the most frequently occurring compression neuropathy in the upper limb next to carpal tunnel syndrome. Recent minimal invasive technique has prompted us to gain clinical experience with simple in situ decompression with minimal skin incision for idiopathic cubital tunnel syndrome. Sixty six consecutive patients with cubital tunnel syndrome were treated using minimal skin incision technique. The mean age of the patients was 49.7 (range: 15-77) years and average follow up period was 23.9 months (range: 12-60 months). The severity of ulnar neuropathy was classified according to the McGowan classification: there were 17 in grade I, 47 in grade II and 2 in grade III. A preoperative nerve conduction study was done by inching method, which revealed motor conduction delay around the medial epicondyle. All operations were carried out in a day surgery unit under local anesthetics. The postoperative outcome was evaluated by Messina classification. The mean duration of the operation was 12 minutes. The technique was highly satisfactorily esthetic for all. Over 80% of the patients were completely satisfied with the procedure taking into consideration their symptoms. Postoperative outcome measures and patient satisfactions (pain, return to normal activities and work, scar and pillar tenderness) were comparable with published series of anterior transposition. The overall satisfactory results were recorded 81% in the patients of McGowan stage I and II. There were 2 cases of hematoma as a postoperative complication. This procedure is comparably effective alternative which involves less surgical trauma, morbidity and rehabilitation time with good surgical outcomes especially in mild and moderate degrees. Minimal skin incision is a simple, safe and effective method to treat patients with idiopathic cubital tunnel syndrome.

The e-health landscape: current status and future prospects in Korea.

The e-health infrastructure in Korea has come a long way within a short period since the establishment of the Korea e-Health Association in 2003 by the Korean Ministry of Commerce, Industry and Energy. Since then, four related government departments in the Ministry of Health and Welfare, Ministry of Information and Communication, Ministry of National Defense, and the Ministry of Science and Technology have also started planning and promoting their own strategies for e-Health applications. We have defined standardization, law and policy planning, human resources development, research and development for e-health products, and international collaboration as the five core pillars for the development of a successful e-health industry. In 2008, through the reorganization of government ministries, e-health has become an even more important growth industry for the Korean economy. Consequently, relevant government ministries have more concrete and robust action plans for realization of e-health in effect.

Percutaneous screw fixation for scaphoid nonunion in skeletally immature patients: a report of two cases.

Nonunion of the scaphoid waist in skeletally immature patients is rarely diagnosed. We report 2 cases of scaphoid nonunion in skeletally immature patients who underwent percutaneous screw fixation without bone graft. In stable nonunions with minimal sclerosis, percutaneous screw fixation without bone graft can be an alternative to the conventional open procedure in skeletally immature patients, with successful union and clinical outcome.