Post-operative infection of endoscopic submucosal dissection of early colorectal neoplasms: a case?controlled study using a Japanese database

What is known and objective Endoscopic submucosal dissection of early colorectal neoplasms (ESD-ECN) is known to be an operation with risk of contamination, possibly requiring pre-operative antimicrobial prophylaxis for the prevention of post-operative infection. However, an evaluation of the need for pre-operative antimicrobial prophylaxis for ESD-ECN has yet to be reported. The objective of this study was to determine whether pre-operative antimicrobial prophylaxis is associated with a reduced incidence of post-operative infection following ESD-ECN. Methods The present retrospective case-controlled study utilized a database built from the medical records of 14 university hospitals throughout Japan. Patients who were admitted and discharged from the hospital from April 2012 to October 2013 and who had undergone ESD-ECN were included in the study. Patients who had been undergone any other operation during their course of hospitalization, and patients who were prescribed antimicrobial agents for reasons other than post-operative infection or for prophylaxis were excluded. Characteristics of the study population, pre-operative antimicrobial prophylaxis and antimicrobial therapy for post-operative infection were investigated. In addition, we compared the characteristics of patients with post-operative infection (PI) and those with no post-operative infection (NPI). Univariate analyses were used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI). Results and discussion We obtained the records of 522 patients who had undergone ESD-ECN from the database. After application of exclusion criteria, 421 patients were enrolled. The post-operative infection rate was 1・2%. Peritonitis was found most to be the most common post-operative infection (44%). Pre-operative antimicrobial prophylaxis was used for 314 patients (75%), with a median duration of 3・0 (range 1-11) days. Cefotiam was most frequently prescribed for pre-operative antimicrobial prophylaxis (56%). Antimicrobial therapies were started 1-10 days after ESD-ECN for a duration of 1-14 days. Pre-operative antimicrobial prophylaxis was not associated with post-operative infection rate, with an OR (95% CI) of 0・73 (0・08-6・61). However, digestive tract perforation was shown to be associated with post-operative infection and had an OR (95% CI) of 17・1 (1・66-176・45). What is new and conclusion Post-operative infection is an exceedingly rare event following ESD-ECN. Pre-operative antimicrobial prophylaxis had no significant effect on post-operative infection following ESD-ECN and thus may be unnecessary. Instead, prevention of digestive tract perforation may be more critical for the decrease in post-operative infections. Univariate analyses of PI vs. NPI

Secure and effective gene delivery system of plasmid DNA coated by polynucleotide

Polynucleotides are anionic macromolecules which are expected to transfer into the targeted cells through specific uptake mechanisms. So, we developed polynucleotides coating complexes of plasmid DNA (pDNA) and polyethylenimine (PEI) for a secure and efficient gene delivery system and evaluated their usefulness. Polyadenylic acid (polyA), polyuridylic acid (polyU), polycytidylic acid (polyC), and polyguanylic acid (polyG) were examined as the coating materials. pDNA/PEI/polyA, pDNA/PEI/polyU, and pDNA/PEI/polyC complexes formed nanoparticles with a negative surface charge although pDNA/PEI/polyG was aggregated. The pDNA/PEI/polyC complex showed high transgene efficiency in B16-F10 cells although there was little efficiency in pDNA/PEI/polyA and pDNA/PEI/polyU complexes. An inhibition study strongly indicated the specific uptake mechanism of pDNA/PEI/polyC complex. Polynucleotide coating complexes had lower cytotoxicity than pDNA/PEI complex. The pDNA/PEI/polyC complex showed high gene expression selectively in the spleen after intravenous injection into mice. The pDNA/PEI/polyC complex showed no agglutination with erythrocytes and no acute toxicity although these were observed in pDNA/PEI complex. Thus, we developed polynucleotide coating complexes as novel vectors for clinical gene therapy, and the pDNA/PEI/polyC complex as a useful candidate for a gene delivery system

Genetic Polymorphisms of IL-17F and TRAF3IP2 Could Be Predictive Factors of the Long-Term Effect of Infliximab against Crohn’s Disease

Background. We aimed to identify certain genes related to response to infliximab (IFX) and biomarkers to predict the IFX effect for Japanese Crohn\u27s disease (CD) patients by performing an association study of single nucleotide polymorphisms (SNPs) in candidate genes in the interleukin-(IL-) 17 signaling pathway with response to IFX after 1 year of treatment. Methods. A total of 103 patients were divided into two groups, responders and nonresponders. Twenty-eight tag SNPs in 5 genes were genotyped. The frequencies of alleles and genotypes of each SNP were compared between responders and nonresponders in three different inheritance models. A genetic test was performed using a combination of the associated SNPs as biomarkers. Results. Multivariate logistic regression analysis indicated that the four variable factors, concomitant use of immunomodulators, penetrating disease, a G/G genotype of rs766748 in IL-17F, and a C/C or C/A genotype of rs1883136 in TRAF3IP2, independently contributed to response to IFX after 1 year of treatment. Genetic test using the polymorphisms of these genes perfectly predicted the responder and nonresponder CD patients with both concomitant use of immunomodulators and penetrating disease. Conclusion. IL17F and TRAF3IP2 are one of IFX-related genes, useful as biomarkers of IFX response, and may be target molecules for new therapeutic drugs

Genetic variants in antioxidant pathway: Risk factors for hepatotoxicity in tuberculosis patients

Tuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in BACH1, and a G/A or A/A genotype at rs4720833 in MAFK independently conferred ATDH susceptibility. Remarkably, the association of the latter two tag SNPs with ATDH susceptibility was highly statistically significant (P = 0.0006) with an odds ratio of 9.730. This study is the first report to demonstrate that NOS2A, BACH1, and MAFK appear to be genetic determinants of ATDH in Japanese patients with TB. Furthermore, a combination of BACH1 and MAFK polymorphisms may be useful as new biomarkers to identify high-risk Japanese TB patients for ATDH

Biodegradable nanoparticles composed of dendrigraft poly-l-lysine for gene delivery

We developed novel gene vectors composed of dendrigraft poly-l-lysine (DGL). The transgene expression efficiency of the pDNA/DGL complexes (DGL complexes) was markedly higher than that of the control pDNA/poly-l-lysine complex. However, the DGL complexes caused cytotoxicity and erythrocyte agglutination at high doses. Therefore, γ-polyglutamic acid (γ-PGA), which is a biodegradable anionic polymer, was added to the DGL complexes to decrease their toxicity. The resultant ternary complexes (DGL/γ-PGA complexes) were shown to be stable nanoparticles, and those with γ-PGA to pDNA charge ratios of >8 had anionic surface charges. The transgene expression efficiency of the DGL/γ-PGA complexes was similar to that of the DGL complexes; however, they exhibited lower cytotoxicity and did not induce erythrocyte agglutination at high doses. After being intravenously administered to mice, the DGL6 complex demonstrated high transfection efficiency in the liver, lungs, and spleen, whereas the DGL6/γ-PGA8 complex only displayed high transfection efficiency in the spleen. Future studies should examine the utility of DGL and DGL/γ-PGA complexes for clinical gene therapy

Development of Effective Cancer Vaccine Using Targeting System of Antigen Protein to APCs.

PURPOSE: To develop a novel cancer vaccine using the targeting system of antigen protein to antigen-presenting cells (APCs) for efficient and safe cancer therapy. METHODS: The novel delivery system was constructed with antigen protein, benzalkonium chloride (BK), and γ-polyglutamic acid (γ-PGA), using ovalbumin (OVA) as a model antigen protein and evaluating its immune induction effects and utilities for cancer vaccine. RESULTS: BK and γ-PGA enabled encapsulation of OVA and formed stable anionic particles at nanoscale, OVA/BK/γ-PGA complex. Complex was taken up by dendritic cell line DC2.4 cells efficiently. We subcutaneously administered the complex to mice and examined induction of IgGs. The complex induced not only Th2-type immunoglobulins but also Th1-type immunoglobulins. OVA/BK/γ-PGA complex inhibited tumor growth of E.G7 cells expressing OVA regularly; administered OVA/BK/γ-PGA complex completely rejected tumor cells. CONCLUSION: The novel vaccine could be platform technology for a cancer vaccine

Quaternary Complexes Modified from pDNA and Poly-l-Lysine Complexes to Enhance pH-Buffering Effect and Suppress Cytotoxicity

We developed a modified complex of pDNA and poly-l-lysine (PLL) by the addition of poly-l-histidine (PLH) and γ-polyglutamic acid (γ-PGA) to enhance its pH-buffering effect and suppress cytotoxicity. The binary and ternary complexes of pDNA with PLL or/and PLH showed particle sizes of approximately 52-76 nm with cationic surface charge. The ternary complexes showed much higher gene expression than the binary complexes with PLL. The mixed solution of PLL and PLH showed higher buffering capacity than PLL solution. The high gene expression of ternary complexes was reduced by bafilomycin A1. These results indicated the addition of PLH to PLL complexes promoted endosomal escape by enhancing the pH-buffering effect. The binary and ternary complexes showed cytotoxicity and blood agglutination because of their cationic surface charge. We therefore developed quaternary complexes by the addition of anionic γ-PGA, which was reported to decrease the toxicity of cationic complexes. In fact, quaternary complexes showed no cytotoxicity and blood agglutination. Also, quaternary complexes showed higher gene expression than ternary complexes regardless of their anionic surface charge. Quaternary complexes showed selectively high gene expression in the spleen after their intravenous administration. Thus, we successfully developed the quaternary complexes with high gene expression and no toxicity