Analysis of Deep Posterior Anal Fistulas by Magnetic Resonance Imaging: Site of Primary Abscess and Extension Patterns According to the Primary Abscess Depth.

OBJECTIVES: The aim of this study was to use magnetic resonance imaging (MRI) to elucidate the site and depth of the primary abscesses associated with deep posterior anal fistulas and their extension patterns. METHODS: We analyzed 176 consecutive patients with deep posterior anal fistulas and classified the fistulas according to whether the MRI-detected site of the primary abscess was at a superficial or a deep external anal sphincter (EAS) level. RESULTS: The distance between the anal center and the primary abscess center was significantly shorter than the length of the EAS and radius at an angle of 45°. In addition, deep posterior anal fistulas with primary abscesses located at the deep EAS level penetrated the EAS significantly more laterally and made external openings at a significantly more lateral site than when the primary abscess was located at a superficial EAS level. CONCLUSIONS: Primary abscesses associated with deep posterior anal fistulas are located in the posterior intersphincteric space or in the EAS muscle itself, not in Courtney's space, as had previously been claimed.

Rules for anal fistulas with scrotal extension.

OBJECTIVES: To evaluate the rules for anal fistulas with scrotal extension, in particular, whether a high transsphincteric or suprasphincteric fistula, of which internal openings are usually located posteriorly, would extend into the scrotum. METHODS: We retrospectively analyzed 446 consecutive male patients who underwent definitive anal fistula surgery. We compared fistulas with scrotal extension according to the location of the internal opening and divided them into anterior and posterior groups. RESULTS: Forty-six (82.1%) of the 56 anal fistulas with scrotal extension had anterior internal openings. After excluding recurrent fistulas, 42 (87.5%) of the 48 anal fistulas with scrotal extension had anterior internal openings. The relative risk of scrotal extension in the anterior group was 14.22 times higher than that in the posterior group (95% CI: 7.43-27.21; p<0.0001). After excluding recurrent fistulas, this relative risk rose to 18.67 (95% CI: 8.18-42.58), (p<0.0001). CONCLUSIONS: Anal fistulas with scrotal extension are mostly low transsphincteric or intersphincteric with anterior internal openings. High transsphincteric or suprasphincteric fistulas rarely extend into the scrotum, except in recurrent cases.

Bone marrow cells enhance liver regeneration after massive hepatectomy in mice.

BACKGROUND: Recent evidence indicates that transplanted autologous bone marrow cells (BMCs) can be converted into functional liver cells. BMC therapy can improve hepatic function and increase the potential for liver regeneration in patients with serious liver damage. We investigated whether BMC therapy influenced liver regeneration after massive hepatectomy in mice. METHODS: Male C57/BL6 mice underwent 70 % hepatectomy, followed by injection of BMCs via the portal vein (PV group), BMCs via the tail vein (IV group), or saline via the portal vein (control group). Analysis of serum enzyme levels and liver histology was performed on postoperative days (POD) 1, 3, and 5. RESULTS: Compared with the control group, the rate of liver regeneration on POD 3 and 5 was significantly higher in the PV group, but not in the IV group. Examination of the mitotic index and Ki-67 labeling index revealed that the increased liver regeneration resulted from stimulation of DNA synthesis. On POD 3, the serum levels of interleukin (IL)-6 and hepatocyte growth factor (HGF) were significantly higher and the expression of IL-6 and HGF mRNA in the remnant liver tended to be higher in the PV group than in the control group. Histological examination showed BMCs in the liver of the PV group, as well as conversion of BMCs into liver cells. CONCLUSIONS: Our findings indicate that the injection of BMCs via the portal vein, but not the injection of BMCs via the tail, enhances liver regeneration after massive hepatectomy in mice.

Natural antisense transcript-targeted regulation of inducible nitric oxide synthase mRNA levels.

Natural antisense transcripts (asRNAs) are frequently transcribed from mammalian genes. Recently, we found that non-coding asRNAs are transcribed from the 3' untranslated region (3'UTR) of the rat and mouse genes encoding inducible nitric oxide synthase (iNOS), which catalyzes the production of the inflammatory mediator nitric oxide. The iNOS asRNA stabilizes iNOS mRNA by interacting with the mRNA 3'UTR. Furthermore, single-stranded 'sense' oligonucleotides corresponding to the iNOS mRNA sequence were found to reduce iNOS mRNA levels by interfering with mRNA-asRNA interactions in rat hepatocytes. This method was named natural antisense transcript-targeted regulation (NATRE) technology. In this study, we detected human iNOS asRNA expressed in hepatocarcinoma and colon carcinoma tissues. The human iNOS asRNA harbored a sequence complementary to an evolutionarily conserved region of the iNOS mRNA 3'UTR. When introduced into hepatocytes, iNOS sense oligonucleotides that were modified by substitution with partial phosphorothioate bonds and locked nucleic acids or 2'-O-methyl nucleic acids greatly reduced levels of iNOS mRNA and iNOS protein. Moreover, sense oligonucleotides and short interfering RNAs decreased iNOS mRNA to comparable levels. These results suggest that NATRE technology using iNOS sense oligonucleotides could potentially be used to treat human inflammatory diseases and cancers by reducing iNOS mRNA levels.

Novel strategy for the control of postoperative pain: long-lasting effect of an implanted analgesic hydrogel in a rat model of postoperative pain.

BACKGROUND: The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is the most common nonopioid analgesic currently used for postoperative pain management. We tested the sustained analgesic effect of ketoprofen emanating from a biodegradable gelatin hydrogel in a rat model of postoperative pain. METHODS: A sheet of analgesic-infiltrated hydrogel was inserted below the plantaris muscle at the end of surgery. Mechanical thresholds were measured by use of von Frey filaments before and 2 weeks after the operation. The effect of ketoprofen on the postoperative pain was also assessed immunohistochemically by assessing microglial activation in the spinal cord with anti-OX-42 and phosphorylated p38 mitogen-activated protein kinase antibodies. RESULTS: Implantation of ketoprofen-infiltrated gelatin hydrogel exerted a sustained analgesic effect for 1 week after the operation. Preemptive analgesia with zaltoprofen, another NSAID, produced an additive analgesic effect in conjunction with the ketoprofen-infiltrated hydrogel. Microglial activation was attenuated by the treatment with ketoprofen-infiltrated hydrogel on day 3 after the incision. CONCLUSIONS: These results demonstrate that ketoprofen was effective in reducing mechanical hypersensitivity for 1 week in a rat model of postoperative pain and that the implantation of NSAID-infiltrated gelatin hydrogel may serve as a useful analgesic method for the long-term relief of patients after surgery.

Japanese herbal medicine, inchinkoto, inhibits inducible nitric oxide synthase induction in interleukin-1ß-stimulated hepatocytes.

AIM: A herbal medicine, kampo inchinkoto (TJ-135), is used to treat jaundice and liver fibrosis in patients with cirrhosis. In the inflamed liver, proinflammatory cytokines stimulate the induction of inducible nitric oxide synthase (iNOS) gene expression. Over-production of nitric oxide (NO) by iNOS has been implicated as a factor in liver injury. We examined interleukin (IL)-1ß-stimulated hepatocytes as a simple in vitro injury model to determine liver-protective effects of TJ-135. The objective was to investigate whether TJ-135 influences iNOS induction and to determine its mechanism. METHODS: Primary cultured rat hepatocytes were treated with IL-1ß in the presence or absence of TJ-135. The induction of iNOS and its signaling pathway were analyzed. RESULTS: IL-1ß produced increased levels of NO. This effect was inhibited by TJ-135, which exerted its maximal effects at 3 mg/mL. TJ-135 decreased the levels of iNOS protein and its mRNA expression. Experiments with nuclear extracts revealed that TJ-135 inhibited the translocation of nuclear factor-κB (NF-κB) to the nucleus and its DNA binding. TJ-135 also inhibited the activation of Akt, resulting in the reduction of type I IL-1 receptor mRNA and protein expression. Transfection experiments with iNOS promoter-luciferase constructs demonstrated that TJ-135 suppressed iNOS induction by inhibition of promoter transactivation and mRNA stabilization. TJ-135 reduced the expression of an iNOS gene antisense-transcript. Delayed administration or withdrawal of TJ-135 after IL-1ß addition also inhibited iNOS induction. CONCLUSIONS: RESULTS indicate that TJ-135 inhibits the induction of iNOS at both transcriptional and post-transcriptional steps, leading to the prevention of NO production. TJ-135 may have therapeutic potential for various liver injuries through the suppression of iNOS induction.

Peroxidation of n-3 Polyunsaturated Fatty Acids Inhibits the Induction of iNOS Gene Expression in Proinflammatory Cytokine-Stimulated Hepatocytes.

Eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA), n-3 polyunsaturated fatty acids (PUFAs), have a variety of biological activities including anti-inflammatory and anticancer effects. We hypothesized that their peroxidized products contributed in part to anti-inflammatory effects. In the liver, the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated as one of the factors in hepatic inflammation and injury. We examined whether the peroxidation of EPA/DHA influences the induction of iNOS and NO production in proinflammatory cytokine-stimulated cultured hepatocytes, which is in vitro liver inflammation model. Peroxidized EPA/DHA inhibited the induction of iNOS and NO production in parallel with the increased levels of their peroxidation, whereas unoxidized EPA/DHA had no effects at all. Peroxidized EPA/DHA reduced the activation of transcription factor, NF-κB, and the expression of the iNOS antisense transcript, which are involved in iNOS promoter transactivation (mRNA synthesis) and its mRNA stabilization, respectively. These findings demonstrated that peroxidized products of EPA/DHA suppressed the induction of iNOS gene expression through both of the transcriptional and posttranscriptional steps, leading to the prevention of hepatic inflammation.

Sivelestat suppresses iNOS gene expression in proinflammatory cytokine-stimulated hepatocytes.

BACKGROUND: Recent evidence has indicated that sivelestat, a neutrophil elastase inhibitor, has liver-protective effects in a variety of liver injuries. Proinflammatory cytokines including interleukin (IL)-1ß stimulate the induction of inducible nitric oxide synthase (iNOS) gene expression, leading to excess production of NO and resulting in liver damage. We hypothesized that inhibition of iNOS induction underlies the protective effects of sivelestat on the liver. The objective of this study was to investigate whether sivelestat directly influences iNOS induction in cultured hepatocytes, which is used as a simple in vitro injury model, and to determine the mechanism involved. METHODS: Primary cultured rat hepatocytes were treated with IL-1ß in the presence or absence of sivelestat. The induction of iNOS and its signaling pathway were analyzed. RESULTS: Sivelestat inhibited the induction of iNOS mRNA and its protein, followed by decreased production of NO. Transfection and iNOS gene antisense-transcript experiments revealed that sivelestat reduced the levels of iNOS mRNA at both the promoter activation and mRNA stabilization steps. However, sivelestat had no effects on the degradation of IκB and nuclear translocation of NF-κB subunit p65, although it moderately blocked the activation of NF-κB. In contrast, sivelestat blocked the upregulation of IL-1 receptor I through the inactivation of phosphatidylinositol 3-kinase/Akt. CONCLUSIONS: Delayed sivelestat addition experiments demonstrated that the destabilization of the iNOS mRNA contributed more significantly to the inhibitory effects of sivelestat than the reduction in iNOS mRNA synthesis. Sivelestat may provide useful therapeutic effects through the suppression of iNOS induction involved in liver injury.

Feasibility and accuracy of second-look laparoscopy after gastrectomy for gastric cancer.

BACKGROUND: A better method for detecting early peritoneal progression is needed. This study evaluated the feasibility and accuracy of second-look laparoscopy for patients with gastric cancer treated using systemic chemotherapy after gastrectomy. METHODS: Second-look laparoscopy was conducted for patients who had no clinical evidence of distant metastases but had peritoneal metastases or positive peritoneal cytology results without visible metastatic disease at initial surgery, patients who underwent systemic chemotherapy over a 6-month period after surgery, and patients who had no clinical evidence of disease based on imaging study after completion of primary chemotherapy. RESULTS: Between November 2004 and April 2008, 21 patients underwent second-look laparoscopy. At the initial surgery, 13 of these patients underwent total gastrectomy and 8 patients underwent distal gastrectomy. One or two sheets of adhesion barrier were received by 18 patients. The median interval between initial surgery and second-look laparoscopy was 9.8 months (range, 6.6-17.5 months). All second-look procedures were completed laparoscopically, and no patients required conversion to laparotomy. None of the 21 patients experienced postlaparoscopy complications. Whereas 12 patients showed no pathologic evidence of disease, 9 patients showed disease at second-look laparoscopy. There was a significant difference in median survival between the groups with negative and positive results (p = 0.017). The median survival for the negative group has not been determined. All the patients in the positive group received further chemotherapy while showing a good performance status (PS). Six patients were PS 0, and 3 patients were PS 1. The median survival time for this group was 10.1 months. CONCLUSIONS: Second-look laparoscopy was a safe and promising approach to reassessment of peritoneal disease for patients with gastric cancer. The incidence of complications was low, particularly in this group of patients, all of whom had undergone prior gastrectomy.

New tubular bioabsorbable knitted airway stent: feasibility assessment for delivery and deployment in a dog model.

PURPOSE: The aim of this study was to determine whether it is possible to deliver and deploy a new device, a poly-L-lactic acid (PLLA) tubular knitted airway stent, under bronchoscopic guidance in a dog model. DESCRIPTION: The delivery system consisted of a flexible balloon catheter (controlled radial expansion balloon dilator, M00558440, Boston Scientific Corporation, MA, USA) preloaded with a stent. A delivery catheter preloaded with a stent was advanced to a target point in the trachea under bronchoscopic guidance. Once the stent was positioned, the balloon was inflated for sixty seconds. The stent was in full contact with the tracheal wall upon deflation of the balloon. EVALUATION: The stents were successfully delivered into the tracheal lumen and successfully deployed in all dogs. CONCLUSIONS: This is the first study to prove the feasibility of delivering and deploying the PLLA stents in a dog model, using a balloon expansion technique. Further investigation with large numbers of subjects and long-term follow-up will be necessary to assess the utility of the bioabsorbable knitted tubular stent before clinical applications begin.