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BackgroundHemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce hemihyperplasia and hemihypoplasia, respectively. Because of their somatic mosaicism, BWS and SRS show a wide spectrum of clinical phenotypes. We evaluated the underlying epigenetic alterations and potential epigenotype-phenotype correlations, focusing on LLD, in a group of individuals with isolated hemihyperplasia/hemihypoplasia.ResultsWe prospectively collected paired blood-tissue samples from 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for LLD. Methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) and bisulfite pyrosequencing for differentially methylated regions 1 and 2 (DMR1 and DMR2) on chromosome 11p15 were performed using the patient samples. Samples from patients showing no abnormalities in MS-MLPA or bisulfite pyrosequencing were analyzed by single nucleotide polymorphism (SNP) microarray andCDKN1CSanger sequencing. We introduced a metric named as the methylation difference, defined as the difference in DNA methylation levels between DMR1 and DMR2. The correlation between the methylation difference and the predicted LLD at skeletal maturity, calculated using a multiplier method, was evaluated. Predicted LLD was standardized for stature. Ten patients (33%) showed epigenetic alterations in MS-MLPA and bisulfite pyrosequencing. Of these, six and four patients had epigenetic alterations related to BWS and SRS, respectively. The clinical diagnosis of hemihyperplasia/hemihypoplasia was not compatible with the epigenetic alterations in four of these ten patients. No patients showed abnormalities in SNP array or theirCDKN1Csequences. The standardized predicted LLD was moderately correlated with the methylation difference using fat tissue (r = 0.53;p = 0.002) and skin tissue (r = 0.50;p = 0.005) in all patients.ConclusionsIsolated hemihyperplasia and hemihypoplasia can occur as a spectrum of BWS and SRS. Although the accurate differentiation between isolated hemihyperplasia and isolated hemihypoplasia is important in tumor surveillance planning, it is often difficult to clinically differentiate these two diseases without epigenetic tests. Epigenetic tests may play a role in the prediction of LLD, which would aid in treatment planning.

Purpose Surgical correction of proximal tibia deformity in small children can be challenging. We present the surgical technique and outcome of proximal tibia osteotomy fixed with small monolateral external fixator in this patient group. Methods A total of 17 cases in eight patients younger than nine years of age were study subjects. A proximal tibia osteotomy was fixed with a small monolateral external fixator with or without cross-pinning. Outcome was evaluated by changes of radiographic parameters such as medial proximal tibia angle (MPTA), metaphyseal diaphyseal angle (MDA) and clinical findings of complications, time interval until weight bearing and fixator removal time. Results MPTA improved from a preoperative mean of 73° (sd 4°; 66° to 78°) to an immediate postoperative mean of 90° (sd 3°; 85° to 96°) in varus tibiae, and from 104° (sd 1°; 103° to 105°) to 89° (sd 1°; 88° to 89°) in valgus tibiae. In all, 15 of the 17 cases (88.3 %) achieved postoperative MPTA within the normal range (85° to 90°). MDA improved from a preoperative mean of 19° (sd 5°; 11° to 24°) to an immediate postoperative mean of 0° (sd 4°; -6° to 7°) in varus tibiae, and from -25° (sd 2°; -22° to -24°) to 2° (SD 1°; 1° to 3°) in valgus tibiae. Full weight bearing was possible at mean 1.7 months (0.5 to 3.0). Mean follow-up period was 6.5 years (sd 5.4; 1.0 to 16.0). No complications developed during the follow-up. Conclusion Proximal tibia osteotomy fixed with small monolateral external fixator provides accurate, safe and efficient correction in the management of coronal plane angular deformity in small children. Level of Evidence Level IV

BACKGROUND: The acetabular index and center-edge angle are widely used radiographic parameters. However, the exact landmarks for measuring these parameters are not clearly defined. Although their measurement is straightforward when the lateral osseous margin of the acetabular roof coincides with the lateral end of the acetabular sourcil, where these two landmarks disagree, recommendations have differed about which landmark should be used. Using a radiographic parameter with high reliability for predicting residual hip dysplasia helps avoid unnecessary treatment. QUESTIONS/PURPOSES: We aimed to (1) compare two landmarks (the lateral osseous margin of the acetabular roof and the lateral end of the acetabular sourcil) for measuring the acetabular index and center-edge angle with respect to intraobserver and interobserver reliability and the predictability of residual hip dysplasia in patients with developmental dysplasia of the hip (DDH) and (2) evaluate longitudinal change in the acetabular edge’s shape after closed reduction with the patient under general anesthesia. METHODS: Between February 1985 and July 2006, we performed closed reduction with the patient under general anesthesia as well as cast immobilization in 116 patients with DDH. To be included in this study, a patient had to have dislocated-type DDH. We excluded patients with a hip dislocation associated with neuromuscular disease, arthrogryposis, or congenital anomalies of other organs or systems (n = 9); hips that underwent osteotomy within 1 year since closed reduction (n = 8); hips that underwent open reduction because of re-dislocation after closed reduction (n = 4); and hips with Type III or IV osteonecrosis according to Bucholz-Ogden’s classification (n = 4). Ninety-one patients were eligible. We excluded 19% (17 of 91) of the patients, who were lost to follow-up before they were 8 years old, leaving 81% (74 of 91 patients) with full preoperative and most-recent data. Ninety-seven percent (72 patients) were girls and 3% (two patients) were boys. The mean ± standard deviation age was 14.0 months ± 6.4 months (range 3-40 months) at the time of closed reduction and 12.1 years ± 2.3 years (range 8.0-16.0 years) at the time of the latest follow-up examination, the duration of which averaged 11 years ± 2.2 years (range 6.5-15.4 years). To investigate whether longitudinal change in the acetabular edge’s shape differed among hips with DDH, contralateral hips, and control hips, we identified control participants after searching our hospital’s database for patients with a diagnosis of congenital idiopathic hemihypertrophy from October 2000 to November 2006 who had AP hip radiographs taken at 3 years old and then at older than 8 years. From 29 patients who met these criteria, we randomly excluded two male patients to match for sex because girls were predominant in the DDH group. We excluded another female patient from the control group because of a hip radiograph that revealed unacceptable rotation. Eventually, 26 patients were assigned to the control group. Control patients consisted of 24 girls (92%) and two boys (8%). The demographic characteristics of control patients was not different from those of 67 patients with unilateral DDH, except for laterality (left-side involvement: 64% [43 of 67] in the DDH group versus 38% [10 of 26] in the control group; odds ratio 1.7 [95% confidence interval, 1.0-2.8]; p = 0.035). The acetabular index and center-edge angle at 3 years old were measured using the lateral osseous margin of the acetabular roof (AI(B) and CEA(B)) and the lateral end of the acetabular sourcil (AI(S) and CEA(S)). The treatment outcome was classified as satisfactory (Severin Grade I or II) or unsatisfactory (Grade III or IV). The intraclass correlation coefficient (ICC) was used to compare the intraobserver and interobserver reliability of each method. We compared the predictability of residual hip dysplasia of each method at 3 years old as a proxy using the area under the receiver operating characteristic (AUC) curve. To evaluate longitudinal change in the acetabular edge’s shape, we compared the proportion of hips showing coincidence of the two landmarks between 3 years old and the latest follow-up examination. To investigate whether the longitudinal change in the acetabular edge’s shape differs among hips with DDH, contralateral hips, and control hips, we compared the proportion of coincidence among the three groups at both timepoints. RESULTS: Intraobserver and interobserver reliabilities were higher for the CEA(B) (ICC 0.96; 95% CI, 0.94-0.98 and ICC 0.88; 95% CI, 0.81-0.92, respectively) than for the CEA(S) (ICC 0.81; 95% CI, 0.70-0.88 and ICC 0.69; 95% CI, 0.55-0.79, respectively). The AI(B) (AUC 0.88; 95% CI, 0.80-0.96) and CEA(B) (AUC 0.841; 95% CI, 0.748-0.933) predicted residual hip dysplasia better than the AI(S) (AUC 0.776; 95% CI, 0.67-0.88) and CEA(S) (AUC 0.72; 95% CI, 0.59-0.84) (p = 0.03 and p = 0.01, respectively). The proportion of hips showing coincidence of the two landmarks increased from 3 years old to the latest follow-up examination in hips with DDH (37% [25 of 67] to 81% [54 of 67]; OR = 8.8 [95% CI, 3.1-33.9]; p < 0.001), contralateral hips (42% [28 of 67] to 85% [57 of 67]; OR = 16.5 [95% CI, 4.2-141.9]; p < 0.001), and control hips (38% [10 of 26] to 88% [23 of 26]; OR = 14 [95% CI, 2.1-592.0]; p = 0.001). The proportion of coincidence in hips with DDH was not different from that in the contralateral hips and control hips at both timepoints. CONCLUSIONS: Measuring the acetabular index and center-edge angle at 3 years old using the lateral osseous margin of the acetabular roof has higher reliability for predicting residual hip dysplasia than that using the lateral end of the acetabular sourcil in patients with DDH treated with closed reduction. Measuring the acetabular index and center-edge angle at an early age using the lateral end of the sourcil may lead to overdiagnosis of residual hip dysplasia and unnecessary treatment. LEVEL OF EVIDENCE: Level III, diagnostic study.

Femoral neck fracture (FNF) is not common in osteogenesis imperfecta patients but may result in serious complications if not properly treated in due time. We present three types of FNF in osteogenesis imperfecta and their characteristics, treatment methods and outcomes. Cases of FNF followed for more than 2 years were selected from the osteogenesis imperfecta database. Medical records and radiographs were reviewed to obtain demographic information and to determine ambulatory status, mode of injury, location of the fracture line, presence of preexisting implants, treatment methods and complications. Outcomes were evaluated according to the radiographic results and ambulatory function. The study investigated 15 FNFs in 10 patients including 1 Sillence type I, 1 type III and 8 type IV. They were either community or household ambulators. The mean age at fracture was 11.7 years. The fractures were followed for an average of 6.3 years. Six fractures were attributed to accidental injuries and nine without noticeable trauma. The fracture pattern was categorized into undisplaced (n = 3), angulated-stable (n = 7) or displaced-unstable (n = 5) types. Five fractures were fixed in-situ using screws or Kirschner wires. Other five fractures were treated by closed reduction and screw fixation and the remaining five fractures were managed by femoral valgus osteotomy. Bony union was achieved, and prefracture ambulatory status was restored in all cases. A high index of suspicion is required in the diagnosis of undisplaced or angulated-stable fractures. Treatment is usually challenging, but a judicious approach considering the fracture pattern and patient characteristics result in successful outcomes. The angulated-stable pattern of fracture is unique in osteogenesis imperfecta patients and requires special attention.

BACKGROUND Osteogenesis imperfecta (OI) can develop a protrusio acetabuli deformity. However, the authors observed a pseudo-protrusio-type acetabular deformity (PPAD) on 3-dimensional computed tomography (3D-CT). Hence, we systematically reviewed 3D-CT and pelvis radiographs of OI patients and report the incidence and patterns of acetabular deformity in OI patients and the associated radiographic signs. METHODS The study included 590 hips of 295 OI patients, who were older than 5 years, and did not have a pelvic fracture. The incidence of a deformed acetabulum (center-edge angle >40 degrees) and its correlation with disease severity were investigated. In 40 hips for which 3D-CT was available, 3-dimensional morphology of the acetabular deformity was analyzed to delineate PPAD. On plain radiographs, PPAD-related signs were determined, focusing on the contour of ilioischial line, iliopectineal line, acetabular line, and their relationship. These radiographic signs were also evaluated in the remaining hips with deformed acetabula that did not have 3D-CT. RESULTS One hundred twenty-three hips of 590 hips (21%) showed deformed acetabula. The incidence of deformed acetabula was significantly associated with disease severity (P

The detection and identification of pathogenic microorganisms are essential for the treatment of osteoarticular infection. However, obtaining a sufficient amount of specimen from pediatric patients is often difficult. Herein, we aimed to demonstrate the effectiveness of the blood culture bottle (BCB) system in pediatric osteoarticular infections. We hypothesized that our BCB culture method is superior to the conventional swab and tissue culture methods in terms of required specimen size, incubation time, and microbial identification rate.We analyzed the prospectively collected data of pediatric patients who underwent surgical treatment for osteoarticular infections between August 2016 and October 2019. Four needles were dipped in the infected fluid or tissue during the surgical procedure as soon as the infected area was exposed and were used to inoculate 2 aerobic pediatric BCBs and 2 anaerobic general BCBs. We also collected 2 conventional swab samples and 2 tissue samples from the identical area. The microbial identification rate and the time required for identification were compared between BCB, swab, and tissue cultures.Forty patients constituted the study group; 13 patients had osteomyelitis, 17 patients had septic arthritis, and 10 patients had both. Of these 40 patients, the microbial identification rate was higher with BCB cultures (27 [68%]) than with swab cultures (18 [45%]; p = 0.004) or tissue cultures (15 [38%]; p0.001). Nine samples (9 patients [23%]) were only positive in the BCB culture. Positive microbial growth was not detected with conventional culture methods when microorganisms did not grow on the BCB culture. Compared with swab culture (4.3 ± 1.1 days; p0.001) or tissue culture (4.4 ± 1.1 days; p0.001), the BCB culture reduced the time required for microbial identification (3.5 ± 0.9 days).In pediatric osteoarticular infections, the BCB culture system improved the microbial identification rate, reduced the time to identification, and permitted a smaller-volume specimen, compared with traditional culture systems.Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Background A high fibular location on plain radiographs has been considered suggestive of a discoid lateral meniscus (DLM). We sought to determine whether the high location of the fibular head observed in DLM patients represents a true pathologic finding. Methods Eighty-two patients with symptomatic DLM who underwent arthroscopic treatment constituted the study group (DLM group). The same number of age-matched patients without DLM (control group) were recruited. The DLM group was further divided according to the presence or absence of a knee extension block (EB) of more than 10 degrees into EB(+) and EB(-) subgroups. We defined the compensated distance to the fibular head (CDF) as the distance from the lateral joint line to the tip of the fibular head divided by the femoral condylar width. CDF values measured on anteroposterior (AP) plain radiographs and sagittal MR images were compared between the DLM and control groups and between the EB(+) and EB(-) subgroups. Results There was no significant difference in the mean preoperative CDF value on either AP plain radiographs or sagittal MR images between the DLM and control groups. However, the mean CDF value on AP plain radiographs was significantly lower in the EB(+) subgroup than in the EB(-) subgroup ( p =0.011). The knee EB disappeared in all patients after arthroscopic treatment when the CDF on AP plain radiographs showed no significant difference between subgroups ( p >0.05). Linear regression analysis revealed that the CDF on AP plain radiographs decreased significantly when knee flexion was increased from 0 to 30 degrees ( p =0.003). Conclusions The high fibular location observed on AP plain radiography in DLM patients was associated with limited knee extension. Altered X-ray beam projection to the flexed knee creates the false appearance of a high fibular location on AP plain radiography.

We report a pure distraction injury of the upper thoracic spine and uncontrolled hyperthermia without an infectious cause. Quad fever appears in the first several weeks to months after a cervical or upper thoracic SCI and is characterized by an extreme elevation in body core temperature beyond 40 °C without an infectious cause. Discriminating between infectious and noninfectious causes is important, and a thorough clinical assessment is required. A 52-year-old male visited the emergency room complaining of back pain with complete paralysis [American Spinal Injury Association (ASIA) A] of both lower extremities after a pedestrian-motor vehicle accident. He had trouble breathing due to a hemothorax and flail chest caused by fractures of the right second to eleventh and left fourth to seventh ribs. A computed tomography scan revealed severe distraction of the T1–2 intervertebral space. A magnetic resonance image showed signal changes in the spinal cord and a clean-cut margin between the T1–2 disc and T2 body. The neurological level of injury was C8 upon the initial neurological assessment. Emergency surgery was performed. C6–T3 posterior instrumentation and an autologous iliac bone graft were performed. After surgery, the core temperature increased gradually to above 38.0 °C on post-trauma day 4 and increased to 40.8 °C on post-trauma day 7. None of the repeated aerobic, anaerobic, or fungal cultures of the blood, tracheal aspirate, line tips, urine, or stool was positive until post-trauma day 21, when Candida tropicalis was identified in the urine culture. On post-trauma day 63, the blood pressure, pulse, and body temperature stabilized and the patient was transferred to the general ward. At post-trauma year 6, the injury state was still complete and the neurological level of injury was changed to C4. Based on the Grand Round case and relevant literature, we discuss the case of pure distraction injury of T1–2 with quad fever. Spinal surgeons should be knowledgeable regarding quad fever as well as the differential diagnoses and treatment strategies.

To provide an engine room of mobile hydraulic vehicle with an effective cooling for the combination set of a radiator, a charge air cooler, and an oil cooler, a 500mm-diameter, axial fan is designed to have a 8,800 m3/hr at a resistance of 20mm Aq static pressure with a sound power level less than 86 LwA. The design parameters of sweep angle amplitude, wavelength of sweep angle change, airfoil type, and stagger angle are examined in terms of fan performance and its sound power generation. The surface curvatures generated by the sinusoidal sweep angle variation in the radial direction are proved to result in quite different flow patterns, thereby different types of specific sound power characteristics at the same flowrate. The acoustic noise sources are examined and discussed by using an acoustic imaging technique.

Background There is a paucity of literature on the use of hip arthroscopy for pathologic conditions in skeletally immature patients. Thus, the indications and safety of the procedure are still unclear. The purpose of this study was to investigate the safety and functional outcomes of hip arthroscopy for pediatric and adolescent hip disorders. We further attempted to characterize arthroscopic findings in each disease. Methods We retrospectively reviewed 32 children and adolescents with hip disorders who underwent 34 hip arthroscopic procedures at a tertiary care children's hospital from January 2010 to December 2016. We evaluated functional limitations and improvement after operation by using the modified Harris hip score (HHS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), subjective pain assessment with a visual analog scale (VAS), and range of hip motion as well as the complications of hip arthroscopy. Arthroscopic findings in each disease were recorded. Results Hip arthroscopy was performed for Legg-Calve-Perthes disease (n = 6), developmental dysplasia of the hip (n = 6), slipped capital femoral epiphysis (n = 5), idiopathic femoroacetabular impingement (n = 6), sequelae of septic arthritis of the hip (n = 3), hereditary multiple exostosis (n = 2), synovial giant cell tumor (n = 3), idiopathic chondrolysis (n = 2), and posttraumatic osteonecrosis of the femoral head (n = 1). Overall, there was a significant improvement in the modified HHS, WOMAC, VAS, and range of hip motion. Symptom improvement was not observed for more than 18 months in four patients who had dysplastic acetabulum with a labral tear (n = 2) or a recurrent femoral head bump (n = 2). There were no complications except transient perineal numbness in five patients. Conclusions Our short-term follow-up evaluation shows that hip arthroscopy for pediatric and adolescent hip disorder is a less invasive and safe procedure. It appears to be effective in improving functional impairment caused by femoroacetabular impingement between the deformed femoral head and acetabulum or intra-articular focal problems in pediatric and adolescent hip disorders.

Introduction The purpose of this study was to introduce a new surgical technique, that involves modified Candy-package wiring followed by IM nailing fixation and to determine the clinical and radiological results obtained in patients with unstable intertrochanteric fractures with a lesser trochanter fragment. Materials and methods This study included 22 patients who were undergone proximal IM nailing with lesser trochanter wiring between January 2014 to June 2015. All patients were treated with minimally invasive technique of candy-package wiring for lesser trochanter fragments. The mean age was 75.8 years (range, 53–88) and average follow-up period was 15.1 months (range, 12–24). Each patient was followed up for a minimum of 12 months and their clinical and radiological results were analyzed. Results The mean period required for fracture union was 16.6 weeks. (range, 8–25) and union was successfully completed in all cases. The WOMAC scores at the last F/U visit (average; 45.4, range; 21–75) were not significantly different to pre-trauma status (average; 36.5, range; 19–59) (p = 0.087). In comparison of ambulatory capacity prior to trauma, ambulatory aggravation was noted in four cases (18.2%), and eighteen cases (81.8%) was sustained walking ability of prior of trauma. Wiring breakage was found in two cases and heterotrophic ossification in one case. There were no functional deficeit related to the radiologic finding in these patients. With regard to postoperative complications, were no cut-outs, breakage, or pullout of screws. Conclusion When surgically repairing unstable intertrochanteric fractures with lesser trochanter comminution using proximal IM nailing method, the modified Candy-packaging wiring technique increases the fixation force at the fracture site. Thus, through this technique, both firm fixation of the lesser trochanter and more stable bony union were obtained.

To better understand the molecular mechanisms underlying the anti-aging properties of water extract of edible bird’s nest (WEBN), the effect of WEBN on oxidative stress-induced matrix metalloproteinase-1 (MMP-1) was assessed in human HaCaT keratinocyte. Upon exposure to H2O2, WEBN inhibited H2O2-induced cytotoxicity and scavenged intracellular reactive oxygen species, down-regulated H2O2-induced MMP-1 mRNA expression, protein expression and activity, and lowered the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinases (JNK), which are the upstream of MMP-1 expression. Furthermore, WEBN inhibited the expression of c-Fos and phospho c-Jun, which are components of the transcription factor activator protein-1 (AP-1), AP-1 transcriptional activity, and AP-1 binding to the MMP-1 promoter. These data indicate that the anti-aging properties of WEBN involve the inhibition of MMP-1 expression via down-regulation of the ERK /JNK and AP-1 pathway.

Background Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, growth deficiency, intellectual disabilities, unusual dermatoglyphic patterns, and skeletal abnormalities. The incidence of hip dislocation in Kabuki syndrome ranges from 18% to 62%. We reviewed the outcomes of management of hip dislocations in patients with Kabuki syndrome with special attention to the diagnostic processes for hip dislocation and Kabuki syndrome. Methods Among 30 patients with mutation-confirmed Kabuki syndrome, we selected six patients who had hip dislocations and reviewed their medical records and plain radiographs. The modes of presentation and diagnostic processes for both hip dislocations and Kabuki syndrome were investigated. The management and treatment outcomes of hip dislocations in patients with Kabuki syndrome were evaluated. Results The average age of patients at the time of diagnosis of hip dislocation was 7.7 months (range, 1 week to 22 months). None of the patients were diagnosed as having Kabuki syndrome at that time. Two patients were treated with a Pavlik harness; one, with closed reduction; two, with open reduction and later pelvic and/or femoral osteotomies; and one, with open reduction combined with pelvic osteotomy. The patients were followed up for 5.8 years on average (range, 2.0 to 10.5 years). The radiologic outcome was graded as Severin IA or IB for three patients who were older than 6 years at the latest follow-up (mean age, 9.9 years; range, 7.8 to 12.4 years). In the remaining three patients younger than 6 years (mean age, 3.8 years; range, 2.7 to 5.3 years), the lateral center edge angle was more than 15°. The clinical diagnosis of Kabuki syndrome was made during follow-up after hip dislocation treatment and confirmed by mutational analysis at a mean age of 4.7 years. The mean interval between the diagnosis of hip dislocation and Kabuki syndrome was 4.0 years. Conclusions The management of hip dislocation by conservative or surgical method showed successful results. Awareness of Kabuki syndrome could lead to an early diagnosis of this rare disease in patients with hip dislocation and allow for early detection of other underlying conditions and multidisciplinary management.

The objective of this study was to elucidate the cytotoxic mechanism of Compound K, with respect to the involvement of reactive oxygen species (ROS) and the mitochondrial involved apoptosis, in HT-29 human colon cancer cells. Compound K exhibited a concentration of 50% growth inhibition (IC(50)) at 20 μg/mL and cytotoxicity in a time dependent manner. Compound K produced intracellular ROS in a time dependent fashion; however, N-acetylcysteine (NAC) pretreatment resulted in the inhibition of this effect and the recovery of cell viability. Compound K induced a mitochondria-dependent apoptotic pathway via the modulation of Bax and Bcl-2 expressions, resulting in the disruption of the mitochondrial membrane potential (Δψ(m)). Loss of the Δψ(m) was followed by cytochrome c release from the mitochondria, resulting in the activation of caspase-9, -3, and concomitant poly ADP-ribosyl polymerase (PARP) cleavage, which are the indicators of caspase-dependent apoptosis. The apoptotic effect of Compound K, exerted via the activation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), was abrogated by specific MAPK inhibitors. This study demonstrated that Compound K-mediated generation of ROS led to apoptosis through the modulation of a mitochondria-dependent apoptotic pathway and MAPK pathway.

High mobility group box 1 (HMGB1) was originally identified as ubiquitously expressed nonhistone DNA-binding protein, but recently, it was found to act as an endogenous danger molecule, which signals danger and traumatic cell death. Previously, the authors showed that HMGB1 is massively released immediately after an ischemic insult and that it subsequently activates microglia and induces inflammation in the postischemic brain. Here, we showed the endogenous danger molecule-like function of HMGB1 in primary cortical cultures. HMGB1 was found to be accumulated in NMDA-treated primary cortical culture media, and media collected from these cultures were able to induce neuronal cell death when added to fresh primary cortical cultures. However, HMGB1-depleted NMDA-conditioned media produced by HMGB1 siRNA transfection or by preincubation with anti-HMGB1 antibody or with HMGB1 A box failed to induce neuronal cell death. Furthermore, siRNA-mediated HMGB1 knockdown substantially suppressed NMDA- or Zn(2+)-induced cell death. It was interesting to find that extracellular HMGB1-induced neuronal apoptosis, as evidenced by TUNEL staining and caspase 3 assay in combination with double immunofluorescence staining. A series of RAGE and HMGB1 co-immunoprecipitation experiments in the presence of SB203580 and PD98059 (p38 MAPK and ERK inhibitors, respectively) demonstrated that RAGE-p38 MAPK and RAGE-ERK pathway might underlie extracellular HMGB1-mediated neuronal apoptosis. These results together with our previous reports regarding microglial activation by extracellular HMGB1 indicate that HMGB1 functions as a novel danger signal, which aggravates brain damage via autocrine and paracrine manners.

alphaB-crystallin is a member of the small heat shock proteins, which is abundantly expressed in various vertebrate tissues including the central nervous system. In our previous report, we showed alphaB-crystallin induction in activated astrocytes in the postischemic brain and in H2O2-treated primary astrocyte cultures. To investigate the functional significance of alphaB-crystallin induction in astrocytes, we generated a stable C6 astroglioma cell line overexpressing alphaB-crystallin. In these cells, hydrogen peroxide-induced apoptosis was reduced by 60% compared to parent cells. Furthermore, the repression of alphaB-crystallin expression by alphaB-crystallin siRNA transfection suppressed this protective effect, indicating that alphaB-crystallin is responsible for the protection against H2O2-induced apoptosis in C6 astroglioma cells. Similar level of aggravation in H2O2-induced apoptosis was observed in primary astrocyte cultures when alphaB-crystallin expression was suppressed by alphaB-crystallin siRNA transfection, confirming the importance of alphaB-crystallin. In addition, the induction of caspase-3 activity after H2O2 treatment was markedly suppressed in alphaB-crystallin-overexpressing cells, and immunoprecipitation proved binding between alphaB-crystallin and partially processed caspase-3 (a p24 intermediate). These results indicate that alphaB-crystallin confers protection against hydrogen peroxide-induced astrocytes apoptosis in part by inhibiting caspase-3 activation.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and one of the commonly prescribed antidepressants. Numerous clinical observations and animal studies indicate that fluoxetine enhances the anticonvulsant potencies of several antiepileptic drugs. In the previous report, we showed that fluoxetine strongly protects against delayed cerebral ischemic injury. In the present study, the authors investigated whether fluoxetine has a beneficial effect on KA-induced neuronal cell death. An intracerebroventricular (i.c.v.) injection of 0.94 nmol (0.2 microg) of KA produced typical neuronal cell death both in CA1 and CA3 regions of the hippocampus. Although, there was no significant difference in the time course or severity of epileptic behavior, the systemic administration of fluoxetine 30 min before KA administration significantly attenuated this neuronal cell death. Fluoxetine was found to suppress neuronal cell loss when injected at 10 mg/kg and the effect was enhanced at 50 mg/kg. Furthermore, this fluoxetine-induced neuroprotection was accompanied by marked improvements in memory impairment, as determined by passive avoidance tests. KA-induced gliosis and proinflammatory marker (COX-2, IL-1beta, and TNF-alpha) inductions were also suppressed by fluoxetine administration. It is interesting to note here that fluoxetine treatment suppressed NF-kappaB activity dose-dependently in KA-treated mouse brains, suggesting that this explains in part its anti-inflammatory effect. Together, these results suggest that fluoxetine has therapeutic potential in terms of suppressing KA-induced pathogenesis in the brain, and that these neuroprotective effects are associated with its anti-inflammatory effects.

Fluoxetine is a selective serotonin reuptake inhibitor that is widely used in the treatment of major depression including after stroke. In this study, we tested whether fluoxetine protects neuronal death in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO). The administration of fluoxetine intravenously (10 mg/kg) at 30 min, 3 hr, or 6 hr after MCAO reduced infarct volumes to 21.2+/-6.7%, 14.5+/-3.0%, and 22.8+/-2.9%, respectively, of that of the untreated control. Moreover, the neuroprotective effect of fluoxetine was evident when it was administered as late as 9 hr after MCAO/reperfusion. These neuroprotective effects were accompanied by improvement of motor impairment and neurological deficits. The fluoxetine-treated brain was found to show marked repressions of microglia activation, neutrophil infiltration, and proinflammatory marker expressions. Moreover, fluoxetine suppressed NF-kappaB activity dose-dependently in the postischemic brain and also in lipopolysaccharide-treated primary microglia and neutrophil cultures, suggesting that NF-kappaB activity inhibition explains in part its anti-inflammatory effect. These results demonstrate that curative treatment of fluoxetine affords strong protection against delayed cerebral ischemic injury, and that these neuroprotective effects might be associated with its anti-inflammatory effects.

Type 5 adenylyl cyclase (AC5) is highly concentrated in the dorsal striatum and nucleus accumbens (NAc), two brain areas which have been implicated in motor function, reward, and emotion. Here we demonstrate that mice lacking AC5 (AC5-/-) display strong reductions in anxiety-like behavior in several paradigms. This anxiolytic behavior in AC5-/- mice was reduced by the D(1) receptor antagonist SCH23390 and enhanced by the D(1) dopamine receptor agonist, dihydrexidine (DHX). DHX-stimulated c-fos induction in AC5-/- mice was blunted in the dorso-lateral striatum, but it was overactivated in the dorso-medial striatum and NAc. The siRNA-mediated inhibition of AC5 levels within the NAc was sufficient to produce an anxiolytic-like response. Microarray and RT-PCR analyses revealed an up-regulation of prodynorphin and down-regulation of cholecystokinin (CCK) in the NAc of AC5-/- mice. Administration of nor-binaltorphimine (a kappa opioid receptor antagonist) or CCK-8s (a CCK receptor agonist) reversed the anxiolytic-like behavior exhibited by AC5-/- mutants. Taken together, these results suggest an essential role of AC5 in the NAc for maintaining normal levels of anxiety.

AlphaB-crystallin, known as a vertebrate lens protein, is a member of the small heat shock proteins (sHSP). AlphaB-crystallin is abundantly expressed in the vertebrate lens and striated muscles and it is also expressed constitutively in other tissues including the central nervous system (CNS). In our previous report, we showed alphaB-crystallin induction in activated astrocytes, which are enriched in the penumbra after transient focal cerebral ischemia. We also reported that alphaB-crystallin is significantly induced in astrocytes in the CA3 region of the hippocampus following KA-induced seizure. Here, we report that the expression of alphaB-crystallin is upregulated in H2O2-treated primary astrocyte cultures, which was prepared from newborn male Sprague-Dawley rats and that the proximal 408 bp of the alphaB-crystallin promoter harboring stress response element (STRE) is responsible for this induction. This effect of H2O2 was found to be virtually abolished by introducing mutations into STRE, and these mutations also impaired increased lens epithelial derived growth factor (LEDGF) binding to STRE after H2O2 treatment. Moreover, LEDGF was induced in primary astrocyte cultures after H2O2 treatment and alphaB-crystallin induction was significantly suppressed by transfecting small interfering RNA (siRNA) targeting LEDGF. Together these results indicate that the H2O2-induced upregulations of alphaB-crystallin in astrocytes are mediated by the LEDGF-STRE interaction on alphaB-crystallin promoter.

P-type thermoelectric Bi0.5Sb1.5Te3 compounds were prepared by the spark plasma sintering method with temperature ranges of 300–420∘C and powder sizes of ∼75 μm, 76–150 μm, 151–250 μm. As the sintering temperature increased, the electrical resistivity and thermal conductivity of the compound were greatly changed due to an increase in the relative density. The Seebeck coefficient and electrical resistivity were varied largely with decreasing the powder size. Subsequently, the compound sintered at 380∘C with the powders of ∼75 μm showed the maximum figure-of-merit of 2.65 × 10−3K−1 and the bending strength of 73 MPa.

Korean ginseng (Panax ginseng C.A. Meyer) has been extensively used as a functional food for thousands of years. This study with the aim to evaluate the potential of P. ginseng flower components as a functional food with medicinal properties resulted in the identification of three new dammarane-type saponins, named floralginsenosides Ka-Kc (1-3), along with seventeen known ones (4-20). Their structures were elucidated on the basis of chemical and spectroscopic methods, and their antioxidant activities were evaluated by the intracellular ROS radical scavenging DCF-DA assay. Among them, floralginsenoside Ka (1) displayed potent scavenging activity with the inhibition value of 64% at 10 microM; and ginsenoside Rb(1) (13), floralginsenoside Kc (3), floralginsenoside Kb (2), vinaginsenoside R(9) (11), majoroside F(1) (12), ginsenoside I (17), and ginsenoside II (18) showed moderate scavenging capacity with the inhibition rate of 28, 33, 35, 35, 35, 38, and 38% at 10 microM, respectively. These results warrant further studies concerning the potential of saponin extracts of P. ginseng flowers for functional foods.

As the design rule of NAND-type memory decreases down to sub 100 nm tech regime, one of important problems is the control of the parasitic transistor phenomenon. The parasitic transistor which causes subthreshold kink at high substrate bias is a common phenomenon for STI (shallow trench isolation) technology, especially for isolation whose pitch needs to be shrunk. To resolve the degradation of device performance by the subthreshold hump, many process solution has been reported (Park, 2000). Furthermore, in the fabrication of nano-scale silicon device, accurate 2D failure analysis is one of the important fields to be solved. In this paper, we present the numerical simulation study of STI implant process factor to suppress anomalous hump effect and investigate feasibility of the application of scanning capacitance microscopy (SCM) and chemical staining method in 2D failure analysis of 70nm NAND flash device

The variations of the vertebral artery (VA) are very diverse in its origin and course. Particularly, the origin of the VA from the part of the aortic arch, distal to the origin of the left subclavian artery (SCA), is very rare. We experienced two cases of this variation. Herein, we describe the two cases and review the relative previous reports, which described this variation. We review the embryologic background and the clinical implication of this variation.

Stronger Neo-Minophagen C (SNMC) is a glycyrrhizin-containing preparation that is approved in Japan for the treatment of chronic hepatic diseases and is marketed in Japan, China, Korea, Taiwan, and India. Glycyrrhizin, a triterpene present in the roots and rhizomes of licorice (Glycyrrhiza glabra) has been shown to have anti-inflammatory, anti-oxidative, and anti-viral effects. In the present study, we demonstrated the marked neuroprotective effects of SNMC in the postischemic rat brain after middle cerebral artery occlusion (MCAO). We used 1 ml/kg of SNMC, which is within the dose range used for the treatment of patients with chronic hepatic disease. The administration of SNMC intravenously at 30 minutes before or 30 minutes and 3 hours after MCAO (60 minutes) reduces mean infarct volumes to 27.0±4.2%, 37.1±12.4%, and 67.8±5.8% of that of untreated controls, respectively. This neuroprotective effect is accompanied by improvements in motor impairment and neurological deficits. The administration of SNMC is shown to suppress microglia activation and neutrophil infiltration in the postischemic brain. In addition, SNMC suppresses lipopolysaccharide-induced nitrite production and proinflammatory cytokine induction in a microglia cell line, BV2. This indicates that the neuroprotective effect of SNMC might be due, at least in part, to an anti-inflammatiory effect. Interestingly, SNMC shows significantly higher neuroprotective potency compared to an equivalent dose of pure glycyrrhizin, in terms of reducing infarct volume and improving neurological deficits. Together these results indicate that SNMC, a glycyrrhizin-containing preparation developed for chronic liver disease, has a marked neuroprotective function in the postischemic brain via its anti-inflammatory effects.