Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis.

INTRODUCTION: We previously demonstrated that synovial sublining macrophages express folate receptor beta (FRß). The aim of this study was to evaluate the efficacy of intra-articular administration of a recombinant immunotoxin to FRß for treating rat antigen-induced arthritis. METHODS: A monoclonal antibody (mAb) to rat FRß was produced by immunizing mice with B300-19 cells (murine pre-B cells) transfected with the rat FRß gene. Recombinant immunotoxin was prepared by conjugating the Fv portion of the anti-rat FRß mAb heavy chain with a truncated Pseudomonas exotoxin A and the Fv portion of the anti-rat FRß mAb light chain. Antigen-induced arthritis was induced through intra-articular injection of methylated bovine serum albumin (mBSA) after two subcutaneous injections of mBSA and complete Freund's adjuvant. Immunotoxin was intra-articularly injected into the arthritis joint every other day for seven days after arthritis onset. Joint swelling was measured and histological scores of inflammation, synovial thickness, cartilage, and bone destruction were determined. Immunohistochemistry was performed to detect osteoclast and osteoclast precursor FRß-expressing macrophages and cathepsin K-positive cells on day 21. RESULTS: Intra-articular administration of the immunotoxin attenuated joint swelling (61% suppression; P < 0.01 compared to the control on day 21) and improved histological findings, particularly cartilage and bone destruction (scores of rats treated with control versus the immunotoxin: 2.2 versus 0.5; P < 0.01), by reducing the number of FRß-expressing macrophages and cathepsin K-positive cells. CONCLUSIONS: Intra-articular administration of an immunotoxin to FRß is effective for improving rat antigen-induced arthritis.

A potential role of hyperbaric oxygen exposure through intestinal nuclear factor-kappaB.

OBJECTIVE: Recent studies have demonstrated the therapeutic effectiveness and pharmacologic mechanisms of hyperbaric oxygen therapy (HBOT) in the treatment of a systemic shock state. To elucidate the in vivo role of HBOT during sepsis, we evaluated the effects of HBOT on intestinal mucosal injury and bacterial translocation after lipopolysaccharide challenge. DESIGN: Experimental study. SETTING: First Department of Surgery and Division of Emergency Care, Kagoshima University School of Medicine, Kagoshima, Japan. SUBJECTS: : Male rats were treated with lipopolysaccharide by an intraperitoneal route or with lipopolysaccharide and HBOT. INTERVENTIONS: The survival rate, small intestinal tissue damage, and bacterial translocation in the HBOT-treated group were compared with those in the untreated group. Moreover, plasma tumor necrosis factor-alpha and nitrite/nitrate concentrations, inducible nitric oxide synthase and myeloperoxidase activities, and nuclear factor-kappaB in ileal mucosa were investigated. HBOT was initiated 3 hrs after lipopolysaccharide challenge and administered as 100% oxygen, at 2.53 x 10 kPa (2.5 atm absolute), for 60 mins. MEASUREMENTS AND MAIN RESULTS: When a sublethal dose of lipopolysaccharide (24 mg/kg) was given, the survival rate was much better in the HBOT-treated group (75%) than in the untreated group (33%). HBOT given 3 hrs after lipopolysaccharide injection (10 mg/kg) also lessened the histologic tissue damage of the terminal ileum and the incidence and magnitude of bacterial translocation to mesenteric lymph nodes at 24 hrs after the lipopolysaccharide injection. Moreover, HBOT was able to reduce mucosal inducible nitric oxide synthase and myeloperoxidase activities and plasma nitrite/nitrate concentrations but not serum tumor necrosis factor-alpha concentrations. Immunohistochemical examination revealed that HBOT specifically modified the mucosal nuclear factor-kappaB activation within 4-6 hrs after the injection. CONCLUSIONS: HBOT performed 3 hrs after lipopolysaccharide challenge alleviates intestinal barrier dysfunction and improves survival rates. Herein, we propose one possible mechanism for these beneficial effects: HBOT can modify the nuclear factor-kappaB activation in the intestinal mucosa and attenuate the sequential nitric oxide overproduction and myeloperoxidase activation. Consequently, bacterial translocation could be potentially decreased. We believe that the present study should lead to an improved understanding of HBOT's potential role in sepsis.

[A case of advanced type 4 gastric cancer with peritonitis dissemination, navel metastasis effectively treated with combined chemotherapy of biweekly paclitaxel (TXL) and TS-1].

The patient was a 44-year-old woman who had unresectable advanced gastric cancer with peritoneal dissemination and navel metastasis (Sister Mary Joseph metastasis). The lesion was considered surgically incurable, so she was placed on neoadjuvant chemotherapy consisting of biweekly TXL (100 mg/m2/day 1, 15) and TS-1 (80 mg/m2/day 1-14) and 2 weeks rest. Before chemotherapy, she could not eat anything because of poor expansion of the stomach and ascites. After the 1st course she could eat half the volume of a normal meal. The only side effect of this treatment was pigmentation of the skin and alopecia. After the 2nd course, she returned home and chemotherapy was continued on an outpatient basis. After the 5th course, the stenosis of colon and ascites had disappeared in a barium enema and CT scan, respectively. The poor expansion of the stomach was slightly improved. She was considered to have responded and underwent total gastrectomy with D2 and transverse colectomy and splenectomy. There were no clear nodules indicating peritoneal dissemination in the intra-operative findings. Intra-operative cytological examination was negative. The depth of the cancer invasion was limited to the subserosal layer and there was no invasion to the colon histologically. There was no lymph node metastasis, but there were a small number of cancer cells obtained diffusely in the omentum and mesocolon. There was no findings of recurrence 5 months later. Biweekly TXL and TS-1 therapy was thought to be an effective chemotherapy against advanced gastric cancer.