Transforming growth factor‐α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase‐1

Background: The effect of transforming growth factor (TGF)‐α on fibrosis varies between cell types and the role of TGF‐α in hepatic fibrosis has not been fully elucidated. Methods: We examined the effect of TGF‐α on hepatic fibrosis using TGF‐α‐expressing transgenic mice fed a methionine‐ and choline‐deficient (MCD) diet and human hepatic stellate cells (HSCs) line LX‐2, rat and human primary HSCs. Results: Although the expression levels of the tissue inhibitor of metalloproteinases‐1 and α1(I) collagen mRNA were unchanged, feeding the TGF‐α transgenic mice the MCD diet resulted in greater expression of the murine functional analogue of matrix metalloproteinase‐1 (MMP‐1), MMP‐13 mRNA and protein and attenuated hepatic fibrosis compared with wild‐type mice. TGF‐α overexpression did not affect the extent of the steatosis, oxidative stress and hepatic inflammation in the MCD diet‐fed mice. The effect of TGF‐α on the fibrogenic and anti‐fibrogenic gene expressions varied between cell types in vitro. TGF‐α increased MMP‐1 mRNA expressions that were completely blocked by gefitinib in LX‐2 cells. The extracellular signal‐regulated kinase (ERK) 1/2, c‐Jun N‐terminal kinase and p38 pathways were involved in MMP‐1 mRNA expression in LX‐2 cells. Although TGF‐α increased the phosphorylation of p38, the p38 inhibitor activated the RAS‐ERK pathway and increased TGF‐α‐induced MMP‐1 mRNA expression, which suggested that there may be a crosstalk between the RAS‐ERK and the p38 pathways in LX‐2 cells. Conclusions: The TGF‐α may attenuate hepatic fibrosis in part because of upregulation of the expression of MMP‐1. The balance between fibrogenic and anti‐fibrogenic gene expression and between the activity of the RAS‐ERK and the p38 pathways may be crucial for the fibrotic process.     

Comparison between resection arthroplasty alone and resection arthroplasty with arthrodesis of the first MTP joint for rheumatoid forefoot deformities

It has been reported that nearly 90% of patients with rheumatoid arthritis (RA) have problems with their feet. Several methods of treating hallux valgus deformity in RA have previously been reported, including arthrodesis and joint resection, and good results have been observed with surgical procedures. In this report, we compare the clinical and radiological outcomes of resection arthroplasty alone (the first method) and resection arthroplasty with arthrodesis of the first MTP joint (the second method) for the treatment of forefoot deformities of RA patients. On clinical assessment, the American Orthopaedic Foot and Ankle Society (AOFAS) scale score significantly improved in both methods; however, the second method gave better results than the first method in relation to the footwear and alignment components. On radiographic assessment, in the first method there were no significant changes in the valgus angle (H–V angle) and the fifth metatarsal bone (M1/5) angle between preoperation and last follow-up. In contrast, these angles were decreased in the second method. One of the most important issues in the treatment of forefoot deformities in RA patients is to correct splaying foot deformity. We believe that the second method, which can correct splaying foot deformity, is currently the most reliable treatment method.     

Long-Term Survival in Patients with Locally Advanced Colon Cancer After <Emphasis Type="Italic">En Bloc</Emphasis> Pancreaticoduodenectomy and Colectomy

Purpose  Surgical indications for colon cancer directly invading the pancreas head are controversial. Methods  Between 1957 and 2007, a total of 12 patients (8 men) underwent pancreaticoduodenectomy combined with right hemicolectomy for colon cancer involving the pancreas head. Results  Mean age was 58 (range, 34–77) years. Fistula formation was observed in five patients (41 percent) preoperatively. Tumor involvement was duodenum only (n = 4), duodenum/pancreas (n = 3), stomach/pancreas (n = 1), duodenum/stomach (n = 2), duodenum/liver (n = 1), and pancreas only (n = 1). Only one postoperative death was encountered. Histologic examination showed malignant invasion to the pancreas head in nine cases (75 percent). Overall one-year, three-year and, five-year survival rates after surgery were 75, 66, and 55 percent, respectively. Five patients (41 percent) survived for more than ten 10 years. Conclusions  Pancreaticoduodenectomy for advanced colon cancer invading the pancreas or duodenum provides favorable long-term survival. Supported by a Grant-in-Aid for Basic Research to Dr. Akio Saiura from the Ministry of Education, Culture, Sports, Science and Technology. Reprints are not available.     

A case of pancreatic abscess associated with colonic fistula successfully treated by endoscopic transgastric drainage using a metallic stent

A 64-year-old man, who had been treated conservatively for acute pancreatitis in another hospital 6 months previously, was admitted to our hospital with abdominal pain and fever. CT scan showed an air-containing fluid collection extending from the pancreatic tail to areas around the descending colon, leading to a diagnosis of pancreatic abscess associated with colonic fistula. We performed EUS-guided placement of a naso-cystic tube and an internal drainage tube stent, through which irrigation with saline was started. Because these tubes did not effectively relieve the symptoms, a covered EMS was placed to facilitate drainage to the stomach. Both the symptoms and signs of infection improved, and a contrast study confirmed disappearance of the abscess and closure of the fistula. He has been well without recurrence of the pancreatic abscess for half a year.     

Ectopic gastric mucosa and pancreatic ducts in the rectum

A 68-year-old woman with fecal occult blood was referred to Dokkyo Medical School Hospital. Colonoscopy demonstrated a flat lesion in the rectum, and endoscopic mucosal resection of the lesion was performed. Histologic examination revealed that it contained ectopic gastric mucosa, which had a gastric foveolar and glandular mucinous phenotype, as demonstrated by immunohistochemistry. Moreover, the lesion also contained CA19-9- and CK7-positive pancreatic duct-like components in the submucosal layer. The present case is the first report to describe ectopic gastric mucosa and pancreatic ducts concurrently arising in the rectum.     

The role of donor CD4(+) T cells in the reconstitution of oral immunity by herpes simplex virus type 1 in severe combined immunodeficiency mice

Severe combined immunodeficiency (SCID) mice with ill-developed Peyer's patches develop neither antibodies nor protection against lethal herpes simplex virus type 1 (HSV-1) infection by oral immunization. However, SCID mice carrying spleen cells from immunocompetent BALB/c mice had serum anti--HSV-1 antibody; anti--HSV-1 IgA antibody was detected in eye wash samples, and the mice were protected against lethal HSV-1 infection (88% survival rate). Western blotting showed that antibodies in SCID mice carrying spleen cells from BALB/c mice recognized 60-kDa HSV-1. The effector cells in transferred spleen cells were CD4(+), not CD8(+), T cells. Donor T cells were detected in the submucosal layer of the gut in SCID mice 1 day after transfer. Rapid movement of donor T cells to the gut may have a role in mucosal immunity to HSV-1. Thus, the normal environment for mucosal immunity develops in SCID mice without prior presence of CD4(+) T cells.     

Mechanisms of acute gain and late lumen loss after atherectomy in different preintervention arterial remodeling patterns

The main mechanism of restenosis after directional coronary atherectomy (DCA) remains obscure. We investigated mechanisms of restenosis after DCA in different coronary artery remodeling patterns. DCA was performed in 51 de novo lesions. The lesions were evaluated by intravascular ultrasound (IVUS) before, immediately after, and 6 months after the procedure. According to the IVUS findings before DCA, we classified the lesions into the following 3 groups: (1) positive (n = 10), (2) intermediate (n = 25), and (3) negative (n = 16) remodeling. We measured lumen area, vessel area, and plaque area using IVUS before DCA, immediately after DCA, and at follow-up. Lumen area increase after DCA was mainly due to plaque area reduction in the positive and intermediate remodeling groups (90 plus minus 15% and 80 plus minus 25% increase in lumen area, respectively), whereas that in the negative remodeling group was due to both plaque area reduction (57 plus minus 22% increase in lumen area) and vessel area enlargement (43 plus minus 33% increase in lumen area). The plaque area increase correlated strongly with late lumen area loss in the positive and intermediate remodeling groups (r = 0.884, p <0.001; r = 0.626, p <0.001, respectively), but the decrease in vessel area was not correlated with lumen area loss. In contrast, both an increase in plaque area and a decrease in vessel area were correlated with late lumen area loss (r = 0.632, p = 0.009; r = 0.515, p = 0.041) in the negative remodeling group. Coronary artery restenosis after atherectomy was primarily due to an increase in plaque in the positive and/or intermediate remodeling groups. However, in the negative remodeling group, late lumen loss might have been caused by both an increase in plaque and vessel shrinkage.     

Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis

Tumor necrosis factor-α (TNF-α) has an essential role in the pathogenesis of rheumatoid arthritis (RA) and has been known to induce the production of several inflammatory molecules in vivo. To analyze in vivo the active mechanism of the TNF-α blocking agent, etanercept, the serum levels of the cytokine interleukin-15 (IL-15) and the chemokines growth-regulated protein-α (Gro-α), and interferon-γ inducible protein-10 (IP-10) in RA patients were measured. Twenty-two patients with RA were administered etanercept once or twice a week for more than 6 months. The clinical and laboratory parameters were measured and serum levels of IL-15, Gro-α, and IP-10 were determined using enzyme-linked immunosorbent assay (ELISA) kits at the baseline and at 3 and 6 months after the initial treatment. Additionally, the production of IL-15 and IP-10 by cultured synovial cells stimulated with TNF-α from RA patients was determined by ELISA. A significant decrease in serum levels of IL-15 and IP-10 was observed at 3 and 6 months after initial treatment with etanercept, but not in those of Gro-α. TNF-α induced production of IP-10, but not IL-15 in cultured synovial cells from RA patients. This study demonstrated for the first time the reduction of IP-10 and IL-15 production in RA patients as active mechanisms of etanercept.