An inflammatory pulmonary insult post-traumatic brain injury worsens subsequent spatial learning and neurological outcomes.

BACKGROUND: Severe traumatic brain injury (TBI) patients are at high risk for early aspiration and pneumonia. How pneumonia impacts neurological recovery after TBI is not well characterized. We hypothesized that, independent of the cerebral injury, pneumonia after TBI delays and worsens neurological recovery and cognitive outcomes. METHODS: Fifteen CD1 male mice were randomized to sham craniotomy or severe TBI (controlled cortical impact [CCI] - velocity 6 m/s, depth 1.0 mm) ± intratracheal lipopolysaccharide (LPS-2 mg/kg in 0.1 mL saline) as a pneumonia bioeffector. Neurological functional recovery by Garcia Neurologic Testing (GNT) and body weight loss were recorded daily for 14 days. On Days 6-14, animals underwent Morris Water Maze learning and memory testing with cued trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial clues present). Intergroup differences were assessed by the Kruskal-Wallis test with Bonferroni correction (p < 0.05). RESULTS: Weight loss was greatest in the CCI + LPS group (maximum 24% on Day 3 vs. 8% [Sham], 7% [CCI], both on Day 1). GNT was lowest in CCI + LPS during the first week. Morris Water Maze testing demonstrated greater spatial learning impairment in the CCI + LPS group vs. Sham or CCI counterparts. Cued learning and long-term memory were worse in CCI + LPS and CCI as compared to Sham. CONCLUSION: A pneumonia bioeffector insult after TBI worsens weight loss and mortality in a rodent model. Not only is spatial learning impaired, but animals are more debilitated and have worse neurologic performance. Understanding the adverse effects of pneumonia on TBI recovery is the first step d patients.

Cerebral Edema and Neurological Recovery after Traumatic Brain Injury Are Worsened if Accompanied by a Concomitant Long Bone Fracture.

Progression of severe traumatic brain injury (TBI) is associated with worsening cerebral inflammation, but it is unknown how a concomitant bone fracture (FX) affects this progression. Enoxaparin (ENX), a low molecular weight heparin often used for venous thromboembolic prophylaxis, decreases penumbral leukocyte (LEU) mobilization in isolated TBI and improves neurological recovery. We investigated if TBI accompanied by an FX worsens LEU-mediated cerebral inflammation and if ENX alters this process. CD1 male mice underwent controlled cortical impact (CCI) or sham craniotomy with or without an open tibial FX, and received either ENX (1 mg/kg, three times/day) or saline for 2 days following injury. Randomization defined four groups (Sham, CCI, CCI+FX, CCI+FX+ENX, n = 10/group). Two days after CCI, neurological recovery was assessed with the Garcia Neurological Test (GNT); intravital microscopy (LEU rolling and adhesion, microvascular leakage) and blood hemoglobin levels were also evaluated. Penumbral cerebral neutrophil sequestration (Ly-6G immunohistochemistry [IHC]) were evaluated post-mortem. In vivo LEU rolling was greater in CCI+FX (45.2 ± 4.8 LEUs/100 µm/min) than in CCI alone (26.5 ± 3.1, p = 0.007), and was suppressed by ENX (23.2 ± 5.5, p = 0.003 vs. CCI + FX). Neurovascular permeability was higher in CCI+FX (71.1 ± 2.9%) than CCI alone (42.5 ± 2.3, p < 0.001). GNT scores were lower in CCI+FX (15.2 ± 0.2) than in CCI alone (16.3 ± 0.3, p < 0.001). Hemoglobin was lowest in the CCI+FX+ENX group, lower than in Sham or CCI. IHC demonstrated greatest polymorphonuclear neutrophil (PMN) invasion in CCI+FX in uninjured cerebral territories. A concomitant long bone FX worsens TBI-induced cerebral LEU mobilization, microvascular leakage, and cerebral edema, and impairs neurological recovery at 48 h. ENX suppresses this progression but may increase bleeding.

A concomitant bone fracture delays cognitive recovery from traumatic brain injury.

BACKGROUND: Brain injury progression after severe traumatic brain injury (TBI) is associated with worsening cerebral inflammation but it is unknown how a concomitant bone fracture (BF) affects this progression. Enoxaparin (ENX) decreases penumbral leukocyte mobilization after TBI and improves neurologic recovery. We hypothesized that a concomitant BF worsens learning/memory recovery weeks after TBI and that ENX improves this recovery. METHODS: CD1 male mice underwent controlled cortical impact or sham craniotomy with or without tibial fracture, receiving either daily ENX (0.8 mg/kg) or saline for 14 days after injury. Randomization defined four groups (Sham, TBI only, TBI + Fx, TBI + Fx + ENX, n = 5/each). Body weight loss and neurologic recovery (Garcia Neurologic Test, max score = 18) were assessed each day. Mouse learning (swimming time [s] and total distance [m] to reach the submerged platform Days 14 to 17 after TBI) and memory (swimming time [s] in platform quadrant after platform removed [probe]) was assessed by the Morris water maze. Ly-6G (cerebral neutrophil sequestration) and glial fibrillary acidic protein were evaluated by immunohistochemistry in brain tissue post mortem. Analysis of variance with Tukey's post hoc test determined significance (p < 0.05). RESULTS: A concurrent BF worsened Garcia Neurologic Test scores post-TBI Days 2 to 4 (p < 0.01) as compared with TBI only, and ENX reversed this worsening on Day 4 (p < 0.01). Learning was significantly slower (greater swimming time and distance) in TBI + Fx versus TBI only on Day 17 (p < 0.01). This was despite similar swimming velocities in both groups, indicating intact extremity motor function. Memory was similar in isolated TBI and Sham which was significantly better than in TBI + Fx animals (p < 0.05). Glial fibrillary acidic protein-positive cells in penumbral cortex were most prevalent in TBI + Fx animals, significantly greater than in Sham (p < 0.05). CONCLUSION: A long BF accompanying TBI worsens early neurologic recovery and subsequent learning/memory. Enoxaparin may partially counter this and improve neurologic recovery.

Early low-anticoagulant desulfated heparin after traumatic brain injury: Reduced brain edema and leukocyte mobilization is associated with improved watermaze learning ability weeks after injury.

BACKGROUND: Unfractionated heparin administered immediately after traumatic brain injury (TBI) reduces brain leukocyte (LEU) accumulation, and enhances early cognitive recovery, but may increase bleeding after injury. It is unknown how non-anticoagulant heparins, such as 2,3-O desulfated heparin (ODSH), impact post-TBI cerebral inflammation and long-term recovery. We hypothesized that ODSH after TBI reduces LEU-mediated brain inflammation and improves long-term neurologic recovery. METHODS: CD1 male mice (n = 66) underwent either TBI (controlled cortical impact [CCI]) or sham craniotomy. 2,3-O desulfated heparin (25 mg/kg [25ODSH] or 50 mg/kg [50ODSH]) or saline was administered for 48 hours after TBI in 46 animals. At 48 hours, intravital microscopy visualized rolling LEUs and fluorescent albumin leakage in the pial circulation, and the Garcia Neurologic Test assessed neurologic function. Brain edema (wet/dry ratio) was evaluated post mortem. In a separate group of animals (n = 20), learning/memory ability (% time swimming in the Probe platform quadrant) was assessed by the Morris Water Maze 17 days after TBI. Analysis of variance with Bonferroni correction determined significance (p < 0.05). RESULTS: Compared with CCI (LEU rolling: 32.3 ± 13.7 LEUs/100 µm per minute, cerebrovascular albumin leakage: 57.4 ± 5.6%), both ODSH doses reduced post-TBI pial LEU rolling (25ODSH: 18.5 ± 9.2 LEUs/100 µm per minute, p = 0.036; 50ODSH: 7.8 ± 3.9 LEUs/100 µm per minute, p < 0.001) and cerebrovascular albumin leakage (25ODSH: 37.9 ± 11.7%, p = 0.001, 50ODSH: 32.3 ± 8.7%, p < 0.001). 50ODSH also reduced injured cerebral hemisphere edema (77.7 ± 0.4%) vs. CCI (78.7 ± 0.4 %, p = 0.003). Compared with CCI, both ODSH doses improved Garcia Neurologic Test at 48 hours. Learning/memory ability (% time swimming in target quadrant) was lowest in CCI (5.9 ± 6.4%) and significantly improved in the 25ODSH group (27.5 ± 8.2%, p = 0.025). CONCLUSION: 2,3-O desulfated heparin after TBI reduces cerebral LEU recruitment, microvascular permeability and edema. 2,3-O desulfated heparin may also improve acute neurologic recovery leading to improved learning/memory ability weeks after injury.

Early heparin administration after traumatic brain injury: Prolonged cognitive recovery associated with reduced cerebral edema and neutrophil sequestration.

BACKGROUND: Early administration of unfractionated heparin (UFH) after traumatic brain injury (TBI) reduces early in vivo circulating leukocytes (LEUs) in peri-injury penumbral brain tissue, enhancing cognitive recovery 2 days after injury. It remains unclear how long this effect lasts and if this is related to persistently accumulating LEUs in penumbral brain tissue. We hypothesized that UFH reduces LEU brain tissue sequestration resulting in prolonged cognitive recovery. METHODS: CD1 male mice underwent either TBI by controlled cortical impact (CCI) or sham craniotomy. Unfractionated heparin (75 or 225 U/kg) or vehicle was repeatedly administered after TBI. Neurologic function (Garcia Neurological Test [maximum score = 18]) and body weight loss ratios were evaluated at 24 hours to 96 hours after TBI. Brain and lung wet-to-dry ratios, hemoglobin levels, and brain LEU sequestration (Ly6G immunohistochemistry) were evaluated 96 hours postmortem. Analysis of variance with Bonferroni correction determined significance (p < 0.05). RESULTS: Compared with untreated CCI animals (24 hours, 14.7 ± 1.0; 48 hours, 15.5 ± 0.7; 72 hours, 15.0 ± 0.8; 96 hours, 16.5 ± 0.9), UFH75 (24 hours, 16.0 ± 1.0, p < 0.01; 48 hours, 16.5 ± 0.7, p < 0.05; 72 hours, 17.1 ± 0.6, p < 0.01; 96 hours, 17.4 ± 0.7, p < 0.05) increased cognitive recovery throughout the entire observation period after TBI. At 48 hours, UFH225 significantly worsened body weight loss (10.2 ± 4.7%) as compared with uninjured animals (5.5 ± 2.9%, p < 0.05). Both UFH75 (60.8 ± 40.9 PMNs per high-power field [HPF], p < 0.05) and UFH225 (36.0 ± 17.6 PMNs/HPF, p < 0.01) significantly decreased brain neutrophil sequestration found in untreated CCI animals (124.2 ± 44.1 PMNs/HPF) 96 hours after TBI. Compared with untreated CCI animals (78.8 ± 0.8%), UFH75 (77.3 ± 0.6%, p = 0.04) reduced cerebral edema to uninjured levels (77.4 ± 0.6%, p = 0.04 vs. CCI). Only UFH225 (10.6 ± 1.2 g/dL) resulted in lower hemoglobin than in uninjured animals (13.0 ± 1.2 g/dL, p < 0.05). CONCLUSIONS: Heparin after TBI reduces tissue LEU sequestration and edema in injured brain for up to 4 days. This is associated with persistent improved cognitive recovery, but only when low-dose UFH is given. Early administration of UFH following TBI may blunt LEU-related cerebral swelling and slow progression of secondary brain injury.

A case of splenic metastasis of ovarian cancer treated with complete laparoscopic splenectomy and transvaginal specimen extraction.

A 61-year-old woman was diagnosed with right inguinal lymph node and splenic metastasis of ovarian serous cystadenocarcinoma. We performed right inguinal lymph node dissection and total laparoscopic splenectomy in the supine position followed by transvaginal specimen extraction (TVSE). First, using three ports, we extracted the right inguinal lymph node. We repaired the posterior wall of the inguinal canal using a mesh plug. We added two ports and displaced the spleen from the retroperitoneum and lifted it using a snake retractor, disconnecting the hilum using an automatic suturing device. Next, the posterior wall of the vagina was intraperitoneally incised. And an Alexis® laparoscopic system was inserted into the vagina. The cap maintained aeroperitoneum, a collection bag was inserted in the abdominal cavity via the vagina, and the spleen was collected. When the spleen was removed from the body, partial fragmentation of the organ was required in the bag. Organ fragmentation was performed only within the bag, and we made sure not to tear the bag. The vaginal wound was laparoscopically sutured. The patient had no operative complications and was able to actively ambulate at the first day after surgery due to a slight postoperative pain. Total laparoscopic splenectomy with TVSE in the supine position may be a safe and feasible method for selected female patients. This technique enables minimally invasive surgery for female patients with splenic disease.

[A case of Barrett's esophageal carcinoma treated with combined therapy].

During a routine health examination, a 50-year-old man was found to have an elevated lesion at the esophagogastric junction. Poorly differentiated adenocarcinoma was diagnosed from the biopsy findings. Computed tomography showed metastases in the mediastinal, intra-abdominal, and paraaortic lymph nodes. The clinical stage diagnosis was cT2, cN4, cM0, cStage IVa. Combination chemotherapy with docetaxel, CDDP, and 5-FU (DCF) was started initially. After 2 courses of DCF, the primary lesion and mediastinal lymph nodes had decreased in size, but the intra-abdominal lymph node had grown. A curative operation with paraaortic lymph node dissection was considered possible; thus, video-assisted thoracoscopic surgery of the esophagus with 3-field lymph node dissection was performed. The final findings revealed Barrett's esophageal carcinoma, EG, 0-III,23×18 mm, mod-por, CT-pT1b (sm3) pN4, sM0, fStage IV. Histologically, the mediastinal lymph node metastases disappeared with chemotherapy, but no reduction was observed in the abdominal lymph nodes. After surgery, 2 courses of combination adjuvant chemotherapy with CDDP and 5-FU were administered along with 50 Gy of radiotherapy. Subsequently, the treatment was changed to tegafur-gimeracil-oteracil potassium alone on an outpatient basis. The patient remains recurrence free 22 months postsurgery.

[A case of small intestinal cancer in the efferent loop of roux-en Y reconstruction after total gastrectomy and liver metastases].

A 61-year-old woman, who had undergone total gastrectomy and distal splenopancreatectomy with Roux-en Y reconstruction for a gastric cancer 16 years earlier, was found primary small intestinal cancer located in intestinal loop of Roux- en Y in gastrointestinal endoscopy for abdominal pain. Computed tomography showed liver metastases which were 8 cm in diameter at lateral segment and 1 cm in diameter at segment 8 of the liver. In the operation, the small intestinal cancer was located in the ρ-anastomosis in the loop of Roux-en Y with the other jejunum fistula. We performed lateral segment hepatectomy, partial hepatectomy of segment 8, partial resection of small intestine including loop of ρ-Roux-en Y, partial resection of transverse colon, and restoration Roux-en Y again. We succeeded in preserving double tract anastomosis at duodenum. Histological examination revealed a moderately differentiated adenocarcinoma of the small intestine and segment 8 of the liver, and angiomyolipoma of lateral segment of the liver. It is extremely rare for small intestinal cancer to arise in a loop of Roux-en Y reconstruction caused by total gastrectomy.

The effect of nicorandil on small intestinal ischemia-reperfusion injury in a canine model.

BACKGROUND: It has been shown that nicorandil, which has both ATP-sensitive K+ (KATP) channel opener-like and nitrate-like properties, has an organ-protective effect in ischemia-reperfusion injury in several experimental animal models. AIMS: We evaluate the effectiveness of nicorandil on warm ischemia-reperfusion injury of the small intestine in a canine model. METHODS: Eighteen beagle dogs were divided into three groups: the control group (n=6); the nicorandil group (n=6), to which nicorandil was injected intravenously before the ischemia; and the glibenclamide group (n=6), to which glibenclamide, which closes the KATP channel and does not suppress the nitrate effect of nicorandil, was orally administered, and then nicorandil was injected in the same manner as in the nicorandil group. Both the superior mesenteric artery and vein were clamped for 2 h. Superior mesenteric artery blood flow, small intestinal mucosal tissue blood flow, intramucosal pH, and histopathological analyses were compared among the three groups. RESULTS: Superior mesenteric artery blood flow, mucosal tissue blood flow and pHi after reperfusion were significantly maintained in the nicorandil in comparison with the control and the glibenclamide groups. The histopathological findings showed less severe mucosal damage after reperfusion in the nicorandil group compared with the other two groups. Between the control group and the glibenclamide group, no significant differences were observed in all those parameters. CONCLUSION: This study suggests that nicorandil has a protective effect on small intestinal IR injury, and activation of KATP channels plays an important role in inhibiting small intestinal IR injury.

The effect of nicorandil on ischemia-reperfusion injury in a porcine total hepatic vascular exclusion model.

BACKGROUND: We evaluated the effectiveness of nicorandil, which has both K(ATP) channel opener-like and nitrate-like properties, in liver ischemia-reperfusion (IR) injury using a porcine total hepatic vascular exclusion (THVE) model. METHODS: Mexican hairless pigs weighing 25-55 kg were used in this study. The animals were divided into three groups. In the nicorandil group (n = 6), a 100 µg/kg bolus of nicorandil was injected intravenously 30 min before the ischemia, and then a continuous infusion (10 µg/kg/min) was administered intravenously for 30 min until just before the ischemia. In the control group (n = 6), a saline solution was injected in the same manner. In the glibenclamide group (n = 6), glibenclamide (0.1 mg/kg), which closes the K(ATP) channel gate, was orally administered 180 min before the hepatic ischemia, and then nicorandil was injected in the same manner as in the nicorandil group. THVE was performed for 120 min, and animals were observed until 360 min after reperfusion. Serum AST and LDH levels, hepatic tissue blood flow (HTBF), and histologic analyses were compared among the three groups. RESULTS: Serum AST and LDH levels in the nicorandil group were significantly lower than in the other two groups after reperfusion, while no significant difference was observed between the control and the glibenclamide groups. HTBF in the nicorandil group was also significantly higher than in the other two groups after reperfusion, while no significant difference was observed between the control and glibenclamide groups. Additionally, histopathologic analyses revealed that the hepatic tissue was better maintained in the nicorandil group than in the other two groups. CONCLUSION: Our results using a porcine THVE model suggest that nicorandil inhibits hepatic IR injury. The K(ATP) channel-opener aspect of nicorandil might be primarily responsible for the hepatoprotective effect.

[Intramucosal colorectal carcinomas treated by surgical resection].

Stage 0 colorectal cancer was found only in the innermost lining of the colon and rectum. Treatments for an early stage colorectal cancer were available including endoscopic polypectomy, endoscopic mucosal resection (EMR) and trans-anal or -sacral local excision, laparoscopy-assisted colectomy and open colectomy. Our study indicated that endoscopic therapy for the early stage colorectal cancer was more advantageous than the conventional operative treatment. Although EMR should be applied for intramucosal carcinomas, 11 intramucosal carcinomas were treated by a surgical resection due to several limitations at our institution.

Hemoperfusion with polymyxin B-immobilized fiber column improves liver function after ischemia-reperfusion injury.

AIM: To investigate the usefulness of direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX therapy) for warm hepatic ischemia-reperfusion (I/R) injury after total hepatic vascular exclusion (THVE) using a porcine model. METHODS: Eleven Mexican hairless pigs weighing 22-38 kg were subjected to THVE for 120 min and then observed for 360 min. The animals were divided into two groups randomly: the DHP-PMX group (n = 5) underwent DHP-PMX at a flow rate of 80 mL/min for 120 min (beginning 10 min before reperfusion), while the control group did not (n = 6). The rate pressure product (RPP): heart rate x end-systolic arterial blood pressure, hepatic tissue blood flow (HTBF), portal vein blood flow (PVBF), and serum aspartate aminotransferase (AST) levels were compared between the two groups. RESULTS: RPP and HTBF were significantly (P < 0.05) higher in the DHP-PMX group than in the control group 240 and 360 min after reperfusion. PVBF in the DHP-PMX group was maintained at about 70% of the flow before ischemia and differed significantly (P < 0.05) compared to the control group 360 min after reperfusion. The serum AST increased gradually after reperfusion in both groups, but the AST was significantly (P < 0.05) lower in the DHP-PMX group 360 min after reperfusion. CONCLUSION: DHP-PMX therapy reduced the hepatic warm I/R injury caused by THVE in a porcine model.

Direct hemoperfusion with a polymyxin B-immobilized cartridge in intestinal warm ischemia reperfusion.

AIM: To investigate the effectiveness of direct hemoperfusion with polymyxin B-immobilized fibers (DHP-PMX therapy) on warm ischemia-reperfusion (I/R) injury of the small intestine. METHODS: The proximal jejunum and distal ileum of mongrel dogs were resected. Warm ischemia was performed by clamping the superior mesenteric artery (SMA) and vein (SMV) for 2 h. Blood flow to the proximal small intestine was restored 1 h after reperfusion, and the distal small intestine was used as a stoma. The experiment was discontinued 6 h after reperfusion. The dogs were divided into two groups: the DHP-PMX group (n = 6, DHP-PMX was performed for 180 min; from 10 min prior to reperfusion to 170 min after reperfusion) and the control group (n = 5). The rate pressure product (RPP), SMA blood flow, mucosal tissue blood flow, and intramucosal pH (pHi) were compared between the two groups. The serum interleukin (IL)-10 levels measured 170 min after reperfusion were also compared. RESULTS: The RPP at 6 h after reperfusion was significantly higher in the PMX group than in the control group (12 174 +/- 1832 mmHg/min vs 8929 +/- 1797 mmHg/min, P < 0.05). The recovery rates of the SMA blood flow at 1 and 6 h after reperfusion were significantly better in the PMX group than in the control group (61% +/- 7% vs 44% +/- 4%, P < 0.05, and 59% +/- 5% vs 35% +/- 5%, P < 0.05, respectively). The recovery rate of the mucosal tissue blood flow and the pHi levels at 6 h after reperfusion were significantly higher in the PMX group (61% +/- 8% vs 31% +/- 3%, P < 0.05 and 7.91 +/- 0.06 vs 7.69 +/- 0.08, P < 0.05, respectively). In addition, the serum IL-10 levels just before DHP-PMX removal were significantly higher in the PMX group than in the control group (1 569 +/- 253 pg/mL vs 211 +/- 40 pg/mL, P < 0.05). CONCLUSION: DHP-PMX therapy reduced warm I/R injury of the small intestine. IL-10 may play a role in inhibiting I/R injury during DHP-PMX therapy.