High-mobility group box 1 protein (HMGB1), which mainly exists in the nucleus, has recently been shown to function as a sentinel molecule for viral nucleic acid sensing and an autophagy regulator in the cytoplasm. In this study, we studied the chaperone-like activity of HMGB1 and found that HMGB1 inhibited the chemically induced aggregation of insulin and lysozyme, as well as the heat-induced aggregation of citrate synthase. HMGB1 also restored the heat-induced suppression of cytoplasmic luciferase activity as a reporter protein in hamster lung fibroblast O23 cells with expression of HMGB1. Next, we demonstrated that HMGB1 inhibited the formation of aggregates and toxicity caused by expanded polyglutamine (polyQ), one of the main causes of Huntington disease. HMGB1 directly interacted with polyQ on immunofluorescence and coimmunoprecipitation assay, whereas the overexpression of HMGB1 or exogenous administration of recombinant HMGB1 protein remarkably reduced polyQ aggregates in SHSY5Y cells and hmgb1−/− mouse embryonic fibroblasts upon filter trap and immunofluorescence assay. Finally, overexpressed HMGB1 proteins in mouse embryonic primary striatal neurons also bound to polyQ and decreased the formation of polyQ aggregates. To this end, we have demonstrated that HMGB1 exhibits chaperone-like activity and a possible therapeutic candidate in polyQ disease.

Background

Cortactin and focal adhesion kinase (FAK) are two important components among actin cross-linking proteins that play a central role in cell migration.

Methods

The aims of this study were to evaluate the expression of cortactin and FAK in normal colorectal mucosa and colorectal adenocarcinoma (CRC) using tissue microarray of 2 mm cores to correlate their expression with other clinicopathological factors and, investigate their prognostic significance.

Results

Twenty (9%) and 24 cases (11%) of normal colorectal mucosa were immunoreactive for cortactin and FAK. In addition, 184 (84%) and 133 cases (61%) of CRCs were immunoreactive for cortactin and FAK, respectively. Cortactin expression was associated with histologic differentiation and FAK expression. Cortactin, but not FAK expression was also correlated with poor overall and relapse-free survival and served well as an independent prognostic factor for poor survival.

Conclusions

Cortactin expression, in association with FAK expression, may plays an important role in tumor progression. Furthermore, it may also be a satisfactory biomarker to predict tumor progression and survival in CRC patients.

Background

To compare the effects of endovascular coiling and neurosurgical clipping in patients with unruptured intracranial aneurysm.

Methods

Sixteen electronic databases were searched for articles published between 1950 and July 2010 to compare clinical outcomes of clipping and coiling. Researchers reviewed all searched articles and extracted data independently. The quality of studies and evidence were evaluated using MINORS and GRADEprofiler, respectively. The odds ratio (OR) was calculated using the inverse variance meta-analysis method for each study outcome. To assess heterogeneity of ORs across cohorts, Cochran’s Q statistic and I2 were used.

Results

Of 4160 studies, 24 were identified (n  =  31865). Clipping resulted in significantly higher disability using the Glasgow Outcome Scale (OR, 2.38; 95% CI, 1.33–4.26) and Modified Rankin Scale (OR, 2.83; 95% CI, 1.42–5.63) when compared with coiling. ORs for complications were also higher with clipping (ORs for neurological and cardiac complications were 1.94 with a 95% confidence interval [CI] of 1.09–3.47 and 2.51 with a 95% CI of 1.15–5.50). Clipping resulted in significantly greater disability in the short term (≤6 m)(OR on the Glasgow Outcome Scale, 2.72; 95% CI, 1.16–6.34), but not in the long term (>6 m)(OR for Glasgow Outcome Scale, 2.12; 95% CI, 0.93–4.84).

Conclusions

Coiling was a better procedure for treatment of unruptured intracranial aneurysm in terms of disability, complications, especially in the short term. Because of the limitations of the reviewed studies, further studies are required to support the present results.

Objectives

To evaluate whether candidate genes in innate immunity are associated with childhood leukemia, we conducted an association study with the 1,536 SNPs in 203 genes related to innate immunity.

Methods

Incident childhood leukemia cases (n=136) aged from 0 to 18 were recruited from three teaching hospitals in Seoul between 2003 and 2006. Non-cancer controls (n=140) were frequency-matched to cases by age and gender. The information on the characteristics of children and their parents were collected by trained interviewers using structured questionnaire. Candidate genes were selected based on SNP databases (CGAP and SNP500 database), and genotype assay was performed using GoldenGate (Illumina) oligonucleotide pool assay (OPA). False discovery rate (FDR), permutation test, and haplotype analyses were used to identify the SNP with significant association with childhood leukemia. Childhood leukemia risk was estimated as ORs and 95% CIs adjusted for age, gender and birth weight.

Results

Fourteen SNPs in 13 genes (LMAN1, TLR4, STAT4, CCR9, MBP, ZP1, C8B, XDH, C7, C1QG, FGF2, LOC390183, and STAT6) were significantly associated with childhood leukemia risk (FDR p-values <0.05). In particular, LMAN1 rs1127220, TLR4 rs11536897, STAT4 rs13020076, CCR9 rs1471962, and MBP rs10514234 were significant in 5,000 permutation tests (Permutation p-value <0.05). The most significant association with childhood leukemia risk was for the LMAN1 rs1127220 that is in the protein-coding region, this finding was also supported by haplotype analysis.

Conclusions

A number of innate immunity related genes are associated with childhood leukemia, suggesting possible links between the innate immunity system and development of the childhood leukemia.

We conducted a case–control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (–17961T>C, –9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8, 95% CI = 1.1–2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2–3.4). An increasing trend in risk was observed for pack-years smoked after birth (Ptrend = 0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (Ptrend = 0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5–5.3) and the presence of at least one smoker in the home (2.3, 1.2–4.4), and the test for interaction was significant (Pinteraction = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04–1.24) and smoking before the pregnancy of the child (1.12, 1.04–1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.

Diagnosis of scabies in young children can be challenging since the morphology and distribution of skin lesions may differ from adults. Therefore, clinicians should keep scabies in mind in their differential diagnosis in a child who presents with severe pruritic, polymorphic skin lesions. Regarding the treatment of scabies, the reported clinical experience with gamma benzene hexachloride (lindane) in young children is quite limited because of its neurotoxicity. However, a recent review suggests that lindane is an excellent alternative drug with minimal risk. We report the case of a 2-month-old male infant with pruritic, erythematous macules, papules, nodules, vesicles, and pustules from the top of the head to the tip of the toes. Initially, he was thought to have impetigo and antibiotics were prescribed. After obtaining a careful history and with the use of skin scraping, he was diagnosed with scabies. He was successfully treated with lindane with no adverse reactions.

OBJECTIVE

To determine the overdose rate of drugs that require renal dose adjustment and factors related with overdose.

SUBJECTS

Total of 23,635,210 records of prescriptions and laboratory data of inpatients at a tertiary teaching hospital for the period from January 2002 to December 2005.

METHODS

A clinical data mart was constructed. A knowledge base containing dose adjusting information about 56 drugs was built. One day dose was compared to the reference dose adjusted to the patient’s renal function.

RESULTS

Considering the patient’s renal function, 5.3% of drug doses were excessive. The overdose rate in the patients with moderate to severe renal insufficiency was 28.2%. Only 25% of physicians were responsible for 50.6% of the overdoses. Of 56 drugs studied, 10 drugs, including ranitidine, amoxicillin, and piperacillin/tazobactam, were involved in 85.4% of the overdoses. The physicians with high overdose rate had patients with more impaired renal function (correlation coefficient = 0.192, P < .001). There were negative correlation between clinical experiences of physician and overdose rate (correlation coefficient = −0.221, P < .001) and workload of prescription (correlation coefficient = −0.446, P < .001), when excluding interns from the analyses. There was positive correlation between workload of prescription and overdose rate (correlation coefficient = 0.361, P < .001).

CONCLUSION

A clinical data mart was useful to analyze the vast amount of electronic hospital data. Drug overdose is quite common among inpatients with renal insufficiency. Only a few drugs are responsible for most of drug overdoses. The physicians’ clinical experience, workload of prescriptions, and patients’ renal function are correlated with drug overdose.

Purpose

IRF-5 is a direct transducer of virus-mediated and TLR-mediated signaling pathways for the expression of cytokines and chemokines which form homodimers or heterodimers with IRF-7. However, direct IRF-5-specific monoclonal antibodies (mAbs) are not available at present. These could be used to further evaluate the functions of IRF-5. In this study, we produced and characterized three mouse mAbs to human IRF-5. The binding of IRF-5 to nuclear import proteins was first identified using a mAb.

Materials and Methods

His-tagged human IRF-5 protein spanning amino acid residues 193-257 was used as an antigen and three mAbs were produced. The mAbs were tested with ELISA, Western blot analysis (WB), immunofluorescent staining (IF), and immunoprecipitation (IP). In addition, the nuclear import protein which carried phosphorylated IRF-5 was identified using one of these mAbs.

Results

MAbs 5IRF8, 5IRF10 and 5IRF24 which reacted with the recombinant His-IRF-5193-257 protein were produced. All mAbs bound to human IRF-5, but not to IRF-3 or IRF-7. They could be used for WB, IF, and IP studies. The binding of phosphorylated IRF-5 to karyopherin-α1 and -β1 was also identified.

Conclusion

Human IRF-5-specific mAbs are produced for studying the immunologic roles related to IRF-5. Phosphorylated IRF-5 is transported to the nucleus by binding to nuclear import proteins karyopherin-α1 and -β1.

This study is a preliminary analysis of the prescription behavior of residents in a teaching hospital, with respect to nephrotoxic drugs during a 2-month period. The overdose rate was 3%. Only 5.1% of the doctors were responsible for 51% of the nephrotoxic drug overdoses.

Much effort has focused on detecting as many adverse drug events (ADEs) as possible, as soon possible. An ADE surveillance system (ADESS) is a computerized surveillance system that detects ADEs automatically, by analyzing medication orders, laboratory results, and medical records. We propose a new ADESS architectural framework using the object-oriented component-based development (OOCBD) methodology to extract and analyze ADEs automatically, with a minimal server-side workload.

Lipopolysaccharide (LPS) triggers deleterious systemic inflammatory responses when released into the circulation. LPS-binding protein (LBP) in the serum plays an important role in modifying LPS toxicity by facilitating its interaction with LPS signaling receptors, which are expressed on the surface of LPS-responsive cells. We have previously demonstrated that high mobility group box 1 (HMGB1) can bind to and transfer LPS, consequently increasing LPS-induced TNF-α production in human peripheral blood mononuclear cells (PBMCs). We report here on the identification of two LPS-binding domains within HMGB1. Furthermore, using 12 synthetic HMGB1 peptides, we define the LPS-binding regions within each domain. Among them, synthetic peptides HPep1 and HPep6, which are located in the A and B box domains of HMGB1, bind to the polysaccharide and lipid A moieties of LPS respectively. Both HPep1 and HPep6 peptides inhibited binding of LPS to LBP and HMGB1, LBP-mediated LPS transfer to CD14, and cellular uptake of LPS in RAW264.7 cells. These peptides also inhibited LPS-induced TNF-α release in human PBMCs and induced lower levels of TNF-α in the serum in a subclinical endotoxemia mouse model. These results indicate that HMGB1 has two LPS-binding peptide regions that can be utilized to design anti-sepsis or LPS-neutralizing therapeutics.