Influence of Polyunsaturated Fatty Acid Intake on Kidney Functions of Rats with Chronic Renal Failure.

Arachidonic acid (ARA), an omega-6 (ω-6) polyunsaturated fatty acid (PUFA), is involved in the development and maintenance of renal functions, whereas docosahexaenoic acid (DHA) is an omega-3 (ω-3) PUFA that has anti-inflammatory effects and attenuates nephropathy. However, their effects on the progression of chronic kidney disease (CKD) remain unknown. The aim of this study was to assess the effects of feeding ARA, DHA, and ARA and DHA-containing diets on rats with 5/6 nephrectomized kidneys. Urine and feces were collected every 4 weeks, and the kidneys were collected at 16 weeks after surgery. Urinary albumin (U-ALB) excretion increased gradually with nephrectomy, but the U-ALB excretion was attenuated by feeding the rats with an ARA + DHA-containing diet. Reactive oxygen species (ROS) levels in the kidneys were lower in the ARA + DHA group than in the other groups. At 4 weeks after surgery, the lipid peroxide (LPO) levels in the plasma of the ARA + DHA groups decreased significantly after surgery compared to the control CKD group, but this did not happen at 16 weeks post-surgery. There was a significant negative correlation between LPO levels in the plasma at 4 weeks and creatinine clearance, and a positive correlation with urinary albumin levels. These results suggest that the combination of ARA and DHA inhibit the progress of early stage CKD.

Updated recommendation on molecular-targeted therapy for metastatic renal cell cancer.

Molecular-targeted therapy was recommended for the systemic therapy of renal cell cancer (RCC) in the RCC guidelines, but these guidelines do not address the order of administration of the multiple presently available agents. There are several aspects that remain unknown regarding the optimal administration order and combination of molecular-targeted drugs. Until the optimal treatment sequence is determined by clinical trials, treatment individualization is required for each patient based on patient and disease characteristics. We herein investigate 12 cases of RCC patients who received axitinib. Axitinib was used as the first-line drug in 4 cases, second-line in 5 cases, third-line in 1 case and as a fourth-line drug in 2 cases. Partial response (PR) was observed in 4 cases (30%) and stable disease in 4 cases (30%) during axitinib treatment, with an overall response rate of 60%. The duration of PR ranged from 6 to 19 months. Based on our cases, axitinib exhibited reasonable therapeutic efficacy as first- as well as second-line treatment. However, more cases are required to draw firm conclusions.

A newly designed anal fistula plug: clinicopathological study in an experimental iatrogenic fistula model.

We report on a clinicopathologic study in an animal model of treatment with a new bioabsorbable polymer plug (BAPP). Over a 2-week period, 6 porcine models, which each had 4 anal fistulae, were created using Blake drains. The pigs were divided into 2 groups: the BAPP-treatment group (n = 12 fistulae) and the control group (n = 12 fistulae). Two weeks later, the pigs were humanely killed, and the perianal sites were excised and examined with gross and pathologic studies. Each fistula in the BAPP group was completely cured. In the pathologic study, the treatment sites had little disarray, few defects in the muscular layer, and small numbers of inflammatory cells. The control group had a significantly greater number of inflammatory cells and microabscesses than the BAPP group. The newly developed BAPP reduced the infection and induced good healing in anal fistulae. The BAPP may be a useful new device for the clinical treatment of anal fistulae.

Different healing process of esophageal large mucosal defects by endoscopic mucosal dissection between with and without steroid injection in an animal model.

BACKGROUND: Stricture formation is one of the major complications after endoscopic removal of large superficial squamous cell neoplasms of the esophagus, and local steroid injections have been adopted to prevent it. However, fundamental pathological alterations related to them have not been well analyzed so far. The aim of this study was to analyze the time course of the healing process of esophageal large mucosal defects resulting in stricture formation and its modification by local steroid injection, using an animal model. METHODS: Esophageal circumferential mucosal defects were created by endoscopic mucosal dissection (ESD) for four pigs. One pig was sacrificed five minutes after the ESD, and other two pigs were followed-up on endoscopy and sacrificed at the time of one week and three weeks after the ESD, respectively. The remaining one pig was followed-up on endoscopy with five times of local steroid injection and sacrificed at the time of eight weeks after the ESD. The esophageal tissues of all pigs were subjected to pathological analyses. RESULTS: For the pigs without steroid injection, the esophageal stricture was completed around three weeks after the ESD on both endoscopy and esophagography. Histopathological examination of the esophageal tissues revealed that spindle-shaped α-smooth muscle actin (SMA)-positive myofibroblasts arranged in a parallel fashion and extending horizontally were identified at the ulcer bed one week after the ESD, and increased contributing to formation of the stenotic luminal ridge covered with the regenerated epithelium three weeks after the ESD. The proper muscle layer of the stricture site was thinned with some myocytes which seemingly showed transition to the myofibroblast layer. By contrast, for the pig with steroid injection, esophageal stricture formation was not evident with limited appearance of the spindle-shaped myofibroblasts, instead, appearance of stellate or polygocal SMA-positive stromal cells arranged haphazardly in the persistent granulation tissue of the ulcer site. CONCLUSIONS: Proliferation of spindle-shaped myofibroblasts arranged in a parallel fashion is likely to play an important role in stricture formation after circumferential mucosal defects by esophageal ESD, which may be related to the thinning of the proper muscle layer in the healing course of the defects. Local steroid injection seems to be effective to prevent the stricture through the modification of this process.

Novel pancreatoenteric reconstruction using a bioabsorbable polymer sheet and biocompatible bond.

BACKGROUND: Pancreatoenteric reconstruction often induces severe complications. Although many techniques have been developed to prevent these complications, no standard technique has yet emerged. We developed a novel technique, sutureless pancreatoenteric anastomosis, that uses a bioabsorbable polymer sheet (BAPS) and biocompatible bond (BCB) to prevent the complications associated with pancreatoenteric anastomosis. We used large animals to investigate whether this technique is suitable for clinical use. MATERIALS AND METHODS: Six pigs were laparotomized under general anesthesia. The body of the pancreas was divided, and the proximal stump was closed by suture. A BAPS coated with BCB was rolled and fixed around the distal pancreatic stump to form a cylinder that was anastomosed to the duodenum without suturing the pancreas. Twenty weeks after the initial operation the operated sites were extirpated and evaluated grossly and histologically. RESULTS: All operated pigs survived without pancreatic juice leakage until they were killed. At 20 wk, the BAPS could not be identified. The pancreatic stump was tightly affixed to the duodenum. Histologic study revealed that the pancreatic stump and duodenal wall were continuous and the main pancreatic duct opened into the lumen of the duodenum. CONCLUSIONS: Sutureless pancreatoenterostomy with BAPS and BCB may be clinically feasible.

A bioabsorbable polymer patch for the treatment of esophageal defect in a porcine model.

BACKGROUND: Although several materials have been used to replace the esophagus, none of the materials appears to be feasible for clinical use. Our group has developed a bioabsorbable polymer that can be used to repair the defects of stomach, small intestine, biliary tract, and veins. In this study, we implanted a bioabsorbable polymer patch (BAPP) into an esophageal defect and we investigated the clinical utility of BAPP and evaluated the process of esophageal regeneration. METHODS: Pigs (n = 9) underwent right thoracotomy under general anesthesia. A 4 × 2-cm oval-shaped portion of the esophageal wall was excised, and a BAPP was implanted at the excision site. Esophageal endoscopy was performed at 2 weeks after the implantation. At 4, 8, and 12 weeks after implantation, the whole esophagus was resected for gross and histological examinations of the graft sites. RESULT: Esophageal endoscopy at 2 weeks revealed a tiny ulceration at the implantation site with no stenosis. At 4 weeks, the epithelium at the graft site was similar to that of the native esophagus, but it lacked a proper muscle layer. At 8 weeks, a rough muscle layer had developed. At 12 weeks, normal mucosa and a proper muscle layer similar to that of the native wall were confirmed. CONCLUSION: BAPP repaired the defective esophageal wall without complications, and a neo esophageal wall identical to the native esophageal wall had formed by 12 weeks after implantation. Hence, this newly designed substitute has the potential for application as a novel treatment for defective esophagus.

Newly designed bioabsorbable substitute for the treatment of diaphragmatic defects.

PURPOSE: Earlier studies have investigated the suitability of various materials and autologous grafts for the repair of diaphragmatic defects. Our group investigated the feasibility of using an artificial diaphragm (AD) to repair wide diaphragmatic defects. METHODS: Twelve pigs were laparotomized and, in each pig, a defect was fashioned by resecting a round 8-cm diameter hole in the left diaphragm. Next, the defect was repaired by implanting an AD. The animals were relaparotomized 8 or 24 weeks after implantation for gross, histological and radiological observation of the implanted sites. RESULTS: All recipient animals survived until killing for evaluation. Chest X-ray examinations showed no differences between the preoperative diaphragms and the grafted diaphragms at 8 and 24 weeks after implantation. At 8 weeks after implantation, the implanted sites exhibited fibrous adhesions to the liver and lungs without deformities or penetrations. Parts of the surface tissue at the graft sites had a varnished appearance similar to those of the native diaphragm. Histology performed at 8 weeks detected no trace of the ADs in the graft sites; however, numerous inflammatory cells and profuse fibrous connective tissue were observed. At 24 weeks after implantation, no differences were found in the thorax between the areas with the grafts and the unaffected areas. Histology of the graft sites in the thorax confirmed growth of mesothelial cells similar to that observed in the native diaphragm. CONCLUSIONS: Artificial diaphragms can be a novel substitute for diaphragmatic repair.

An extrahepatic bile duct grafting using a bioabsorbable polymer tube.

BACKGROUND: Thus far, no ideal substitutions have been developed for completely replacing the extrahepatic bile duct (EHBD). METHODS: We used a bioabsorbable polymer tube (BAPT) for the complete reconstruction of an EHBD in pigs. A 2-cm-long EHBD was resected from the duodenal side, and a 4-cm-long BAPT graft was implanted at that site. The animals were re-laparotomized at 1 or 4 months after the grafting; subsequently, gross, histological, and blood chemical studies were performed. RESULTS: At 1 month after grafting, tubular structure was observed in all resected specimens, and the lumen of the graft site had remnants of degraded BAPT. Gross examination at 4 months after grafting revealed that the BAPT had been completely absorbed, and the graft site was indistinguishable from the native extrahepatic bile duct. The lengths of the graft region at 4 months were 70% of the replaced BAPT. Simultaneously performed histological examination revealed the growth of a neo-bile duct at the graft site, with an epithelium identical to that of the native bile duct. CONCLUSION: The BAPT graft implanted in this study completely replaced the EHBD defect. Hence, BAPT has the potential for application as a novel treatment modality for hepatobiliary diseases.

Pringle maneuver induces hepatic metastasis by stimulating the tumor vasculature.

BACKGROUND/AIMS: The Pringle maneuver is traditionally used to avoid hemorrhage during hepatectomy for hepatic metastasis. However, metastasis can occur under ischemic conditions due to some unknown mechanism. METHODOLOGY: An orthotopic model of murine colon cancer was established in syngeneic BALB/c mice. Viable CT-26 cells were implanted into the spleen of these mice. The mice underwent a laparotomy 5 days after the implantation and the hepato-duodenal ligament was clamped for 0 or 10 minutes (Pringle maneuver). The mice were sacrificed 7 days after this maneuver and the number of hepatic metastasis were counted. RESULTS: The mice that underwent the maneuver developed a greater number of hepatic metastasis. An immunohistochemical analysis revealed that the expression of microvessel density, VEGF and KDR/Flk-1 were higher in the hepatic metastasis in the mice treated with the maneuver. In addition, the mice which were treated by the maneuver had a higher level VEGF in the serum. CONCLUSION: These data suggest that the Pringle maneuver induces hepatic metastasis by stimulating the overexpression of tumor vasculature.

Development of a novel reflux-free bilioenteric anastomosis procedure by using a bioabsorbable polymer tube.

BACKGROUND: Bilioenteric anastomosis allows reflux of bowel fluid into bile ducts, resulting in reflux cholangitis. We sought to develop a reflux-free procedure of bilioenteric anastomosis endowed using an artificial bile duct (ABD). METHODS: The study was performed in four groups of pigs. In Group A, end-to-side choledochoduodenostomy using the interposed ABD with its distal end wrapped by the duodenal seromuscular layer was performed. In Group B, conventional end-to-side choledochoduodenostomy using the ABD was performed. In Group C, conventional end-to-side choledochoduodenostomy was performed. In Group D, sham operation was performed. In each groups, 12 weeks later, animals were evaluated. RESULTS: Bile amylase levels were significantly lower in Group A (36.9 +/- 21.7 U/L) compared with Group B (469 +/- 140.9 U/L). No significant differences were observed in bile amylase levels between Groups A and D or between Groups B and C. On histology, the neo-bile duct in Group A was covered with the duodenal muscular layer at the orifice into the intestinal tract. CONCLUSION: This study suggests that the ABD is useful in the regeneration of extrahepatic bile ducts and that to bury the ABD in the duodenum can be a preventive measure against reflux of bowel fluid to bile ducts.

A novel treatment for bile duct injury with a tissue-engineered bioabsorbable polymer patch.

BACKGROUND: With the recent widespread use of laparoscopic cholecystectomy and living-donor liver transplantation, complications involving the biliary system, and stenosis in particular, are encountered frequently. Although various invasive and noninvasive techniques are now available for the treatment of biliary stenosis, recurrence and other problems limit their value and utility. Our group sought to investigate whether a bioabsorbable polymer (BAP) patch could serve as a novel treatment for biliary stenosis. METHODS: In anesthetized hybrid pigs (n = 12), a spindle-shaped portion of the lower common bile duct wall was excised, and a BAP patch was implanted at the excision site. The animals underwent repeat laparotomy at 5 weeks (n = 6) and at 4 months (n = 6) after implantation to recover the graft sites for gross and histologic studies. Blood chemistry was analyzed from samples taken during the patch implantation and recovery. RESULTS: All of the recipient pigs survived until killing. All gained weight and showed no evidence of jaundice. The BAP-patched duct remained patent without obstruction at 5 weeks postimplantation. Blood chemistry did not reveal any increases in hepatobiliary enzyme activities. Histology showed accessory glandular structures in the neo-bile duct. At 4 months, the graft site was indistinguishable from the native duct. Intra-operative cholangiography revealed dilation of the patched site, but no dilatation of the intrahepatic bile ducts. Blood chemistry values were within normal ranges. Histology at the site of the patch confirmed the growth of a cuboidal columnar epithelium similar to that of the native duct. CONCLUSION: The bile duct was dilated only focally at the site of implantation. This newly designed substitute has potential for application as a novel treatment for biliary injury and stenosis.

Regeneration of the inferior vena cava with a bioabsorbable polymer implant: a histological study.

BACKGROUND: Cell implantation into ischemic regions has recently been introduced as a novel strategy for therapeutic angiogenesis. Little is known, however, about the process of blood vessel regeneration, particularly that of the inferior vena cava (IVC). The indicators of normal angiogenesis are also unestablished. PURPOSE: To investigate the process of regeneration of the IVC from a histological viewpoint and to speculate on how the new formation and regeneration of the blood vessels proceed. MATERIALS AND METHODS: Our previous studies showed that a bioabsorbable polymer patch implanted into the IVC formed vessels resembling the native IVC (J Gastrointest Surg 2005;9:789). Using this model system, we investigated the histology and time course of IVC regeneration in the graft site. A 3 x 2 portion of infrahepatic IVC was substituted by a bioabsorbable polymer patch of the same size in hybrid pigs. The patched area was excised for histology at 2 weeks and 3, 6, and 12 months after implantation (n = 3, each). RESULTS: By 2 weeks, the patched area had developed vascular endothelial cells of the same type seen in native veins. The polymer implant was still detectable at 2 weeks but histologically absorbed at 3 months. Smooth muscle was barely formed at 2 weeks, but the ratio of smooth muscle to subendothelial connective tissue gradually increased as time advanced to 3, 6, and 12 months. Even at the last observation at 12 months, however, the amount of smooth muscle formed made up no more than one-half of the native IVC. The case with the elastic fibers accounted for about 90% of the total number of native fibers at 12 months. On gross examination, the patched area resembled the native IVC at 3 months after implantation. CONCLUSION: These results demonstrated that the subendothelial tissue regenerated gradually, requiring more than 1 year to resemble native tissue, whereas the vascular endothelium regenerated in the early phase after injury. Our findings make it possible to establish criteria by which to evaluate venous regeneration.