Operative Procedure for Laparoscopy-Assisted Vagus Nerve and Pylorus-Preserving Gastrectomy (LAVNPPG) for Early Gastric Cancer

Laparosocpy-assisted pylorus-preserving gastrectomy (LAPPG) is a widely accepted surgical procedure for the treatment of early gastric cancer in the middle third of the stomach. We have been performing this operation since 2007. Compared with traditional distal gastrectomy, LAPPG has postoperative nutritional benefits for patients. However, this procedure preserves only the pyloric branch of the vagus nerve and not the celiac branch. We found that patients retain a large amount of residual food in the gastric remnant, which interferes with the detection of secondary cancer on endoscopic follow-up. To improve the pyloric function and postoperative gastrointestinal motility, we changed our procedure during 2009 to preserve both the pyloric and celiac branches of the vagus nerve, and we named this new procedure laparoscopy-assisted vagus nerve and pylorus-preserving gastrectomy (LAVNPPG). From 2009 to 2011, 11 patients underwent LAVNPPG at our hospital. Retrospective comparison of the safety of operation, postoperative complications, and condition of the gastric remnant between LAPPG (n = 13) and LAVNPPG (n = 11) found that the occurrence of postprandial stasis and food residue in the gastric remnant tended to be lower following LAVNPPG, though the differences were not significant. These findings indicate that LAVNPPG may be an operative procedure that could replace LAPPG.     

BLM-DNA2-RPA-MRN and EXO1-BLM-RPA-MRN constitute two DNA end resection machineries for human DNA break repair

Repair of dsDNA breaks requires processing to produce 3'-terminated ssDNA. We biochemically reconstituted DNA end resection using purified human proteins: Bloom helicase (BLM); DNA2 helicase/nuclease; Exonuclease 1 (EXO1); the complex comprising MRE11, RAD50, and NBS1 (MRN); and Replication protein A (RPA). Resection occurs via two routes. In one, BLM and DNA2 physically and specifically interact to resect DNA in a process that is ATP-dependent and requires BLM helicase and DNA2 nuclease functions. RPA is essential for both DNA unwinding by BLM and enforcing 5' → 3' resection polarity by DNA2. MRN accelerates processing by recruiting BLM to the end. In the other, EXO1 resects the DNA and is stimulated by BLM, MRN, and RPA. BLM increases the affinity of EXO1 for ends, and MRN recruits and enhances the processivity of EXO1. Our results establish two of the core machineries that initiate recombinational DNA repair in human cells.     

Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant

Two GATA1-related leukemias have been described: one is an erythroleukemia that develops in mice as a consequence of diminished expression of wild-type GATA1, whereas the other is an acute megakaryoblastic leukemia (AMKL) that arises in Down syndrome children as a consequence of somatic N-terminal truncation (ΔNT) of GATA1 . We discovered that mice expressing the shortened GATA1 protein (ΔNTR mice) phenocopies the human transient myeloproliferative disorder (TMD) that precedes AMKL in Down syndrome children. In perinatal livers of the ΔNTR mutant mice, immature megakaryocytes accumulate massively, and this fraction contains cells that form hyperproliferative megakaryocytic colonies. Furthermore, showing good agreement with the clinical course of TMD in humans, ΔNTR mutant mice undergo spontaneous resolution from the massive megakaryocyte accumulation concomitant with the switch of hematopoietic microenvironment from liver to bone marrow/spleen. These results thus demonstrate that expression of the GATA1/Gata1 N-terminal deletion mutant per se induces hyperproliferative fetal megakaryopoiesis. This mouse model serves as an important means to clarify how impaired GATA1 function contributes to the multi-step leukemogenesis.     

HBO and gas embolism

Gas embolism, which occurs with the entry of gas into the circulatory system from the vein, artery or both, is a potentially serious even fatal condition. The two main causes of gas embolism are iatrogenic and diving. The site of entry and the signs and symptoms distinguish between arterial and venous embolism. The entering gas may be air, but may also be CO(2) or other gases, especially in iatrogenic embolism. Supportive care is the primary therapy for venous gas embolism, while hyperbaric oxygen therapy in addition to supportive care is the first line of treatment for arterial gas embolism. In this article, we will review the pathophysiology, etiology, diagnosis and treatment of gas embolism.     

Regular exercise reduces 8-oxodG in the nuclear and mitochondrial DNA and modulates the DNA repair activity in the liver of old rats

Exercise is often said to increase the generation of reactive oxygen species that are potentially harmful. On the other hand, regular exercise has various health benefits even late in life. The specific aim of this study was to explore effects of regular exercise on oxidative status of DNA in aged animals. We report that 2 months of regular treadmill running of aged rats (21 month old) significantly reduced 8-oxodG content to the level of young adult animals (11 month old) in both nuclear and mitochondrial DNA of the liver. The mitochondrial DNA showed 10-fold higher content of the oxidative lesion than the nuclear DNA. The levels in old animals were 2- and 1.5-fold higher than that in young adults for the nucleus and mitochondria, respectively. The activity of the repair enzyme OGG1 was upregulated significantly in the nucleus but not in mitochondria by the exercise. To our knowledge, this is the first report demonstrating that regular exercise can reduce significantly oxidative damage to both the nuclear and mitochondrial DNA. We suggest that the apparent beneficial outcomes in reducing the DNA damage by regular exercise can be interpreted in terms of hormetic effect by moderate oxidative stress and potential adaptation to stronger stresses.     

High-frequency oscillation (HFO) prevents activation of NF-kappaB found with conventional mechanical ventilation (CMV) in surfactant-depleted rabbit lung

High-frequency oscillation (HFO) has been recognized as an effective ventilatory strategy to minimize lung injury during respiratory support. Conventional mechanical ventilation (CMV) compared with HFO was shown to result in an increased number of PMNs and inflammatory cytokines in the lung lavage fluid. However how mechanical forces can be sensed by cells and converted into biochemical signals for intracellular signal transduction is still unknown. In this current study, we sought to determine whether the activation of Nuclear factor-kappa B (NF-kappaB) might be involved in the lung injury caused by CMV. Surfactant-depleted Japanese white rabbits received 1- or 4-hr CMV or 1- or 4-hr HFO. Then, activation of NF-kappaB in the lungs was assessed by conducting electrophoretic mobility shift assays (EMSA). In the experiment with whole lungs, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs. To clarify the origin of the cells in which NF-kappaB was activated, we did a second lung lavage at the end of ventilation and washed out the cells that had infiltrated the alveoli. The levels of NF-kappaB activity were the similar in the lungs of 4-hr HFO rabbits and in those of 4-hr CMV ones. On the other hand, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs in the experiment with the lung lavage fluid cells. These results show that the increase in NF-kappaB activity in the lungs of 4-hr CMV rabbits was due mainly to the cells that had infiltrated the alveoli.     

Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer

Combination chemotherapy with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) or irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) has become a standard regimen for advanced or recurrent colorectal cancer. Numerous studies have reported that long-term use of FOLFOX or FOLFIRI leads to better survival for these patients. Thus, control of the toxicity of these drugs may be crucial to prolonging survival. Fucoidan is one of the major sulfated polysaccharides of brown seaweeds and exhibits a wide range of biological activities. In the present study, we analyzed the effect of fucoidan on suppressing the toxicity of anti-cancer drugs. A total of 20 patients with unresectable advanced or recurrent colorectal cancer scheduled to undergo treatment with FOLFOX or FOLFIRI were randomly allocated into a fucoidan treatment group (n=10) and a control group without fucoidan treatment (n=10). Results showed that fucoidan regulated the occurrence of fatigue during chemotherapy. Chemotherapy with fucoidan was continued for a longer period than chemotherapy without fucoidan. Additionally, the survival of patients with fucoidan treatment was longer than that of patients without fucoidan, although the difference was not significant. Thus, fucoidan may enable the continuous administration of chemotherapeutic drugs for patients with unresectable advanced or recurrent colorectal cancer, and as a result, the prognosis of such patients is prolonged.     

Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4^−/− mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2^−/− mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2^−/− mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood–brain barrier. Thus, PGE₂ exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood–brain barrier through EP4.