Raisuke Nishiyama

Hepatic release of endothelin-1 after warm ischemia. Reperfusion injury and its hemodynamic effect.

This study investigated the release of endothelin (ET)-1 from the liver after warm ischemia/reperfusion (I/R) injury. Wistar rats were subjected to 120 min of warm hepatic ischemia by clamping the hepatic hilum under porto-jugular shunting. Reperfusion was performed by unclamping. The rats were divided into 2 groups receiving intravenous treatment with an anti-ET-1 mAb before ischemia (AET group) and with mouse immunoglobulin G (sham group). Hepatic blood flow was assessed by laser-Doppler flowmetry and reflectance spectrophotometry and was compared between the 2 groups along with the bile flow rate. The ET-1 concentrations of hepatic venous and portal blood were determined in the sham group, and the portal blood endotoxin levels were assayed in both groups. Both groups developed transient hypotension after reperfusion, but hepatic blood flow subsequently showed a significant improvement in the AET group. Hepatic congestion was detected in the sham group by both reflectance spectrophotometry and histological examination. After reperfusion, bile flow was significantly greater in the AET group. The portal endotoxin concentration showed no increase in both groups, and the hepatic venous blood ET-1 level in the sham group was significantly higher until 3 hr after reperfusion compared to the portal blood level. The 30-day survival rate was 50% in the AET group, whereas all the sham rats died within 12 hr. ET-1 was released from the liver after I/R injury and apparently participated in systemic and local hemodynamic changes that affected survival.

Platelet-activating factor in hepatic ischemia/reperfusion injury. The effects of a PAF antagonist combined with a prostaglandin I2 analogue.

The effects of TCV-309, a specific platelet-activating factor (PAF) antagonist, and OP-41483, a prostaglandin I2 analogue, on warm ischemia/reperfusion injury of the rat liver were studied. Rats were divided into five groups by the duration of warm ischemia and the treatment used. The NS1 group (normal saline pretreatment) had 60 min of warm ischemia, while the NS2 group (normal saline pretreatment), the PGI2 group (OP-41483, 500 ng/kg/min pretreatment), the TCV group (TCV-309, 3 micrograms/kg), and the PGI2+TCV group (both the above dosages) underwent 120 min of warm ischemia. Postoperative survival after 30 days, bile secretion, serum endotoxin levels, and tissue glutathione levels after 60 min of reperfusion were compared between the groups. The survival rates for the NS1, NS2, PGI2, TCV, and PGI2+TCV groups were 80%, 0%, 50%, 80%, and 86.7%, respectively. Bile secretion, which has a strong correlationship with hepatic cellular ATP level, was strongly correlated with survival. The NS2 group had a high serum endotoxin level--however, the PGI2 and PGI2+TCV groups had normal levels. Although there were some discrepancies between survival and the tissue glutathione level, combined treatment with the PGI2 analogue and TCV-309 was most effective in inhibited oxidative stress. In conclusion, TCV-309 increased the survival rate after 120 min of warm hepatic ischemia without endotoxemia by the PGI2 analogue. This finding suggest that warm ischemia/reperfusion injury is related to the generation of PAF. Combined pretreatment with TCV-309 and a PGI2 analogue may be useful in liver transplantation.

Aggressive repeat liver resection for hepatic metastases of colorectal carcinoma.

Although hepatectomy for liver metastases from colorectal carcinoma is an effective treatment, recurrence in the liver is still the most common site after hepatectomy. Thirty patients underwent hepatectomy for hepatic metastases and 17 of them had recurrence in the remnant liver during the following 12-year period. Six of the 17 patients underwent a removal of isolated hepatic recurrences. Two of the six patients underwent a third hepatectomy, and three patients underwent partial lung resection on a total of five occasions. There were no operative deaths while complications after a third hepatectomy contributed to a high morbidity rate of 40 per cent. The mean length of survival of the six patients was 28.5 months from the second hepatectomy. The prognosis of the six patients who underwent a repeat hepatectomy was significantly better than that of patients with unresectable recurrence after an initial hepatectomy (p<0.01). The overall 5-year survival of 29 patients excluding one inhospital death was 44.7 per cent. Our results reveal that aggressive removal of isolated and resectable recurrent disease has the potential to improve the prognosis of selected patients with metastatic cancer.

Portal vein thrombosis after splenectomy successfully treated by an enormous dosage of fibrinolytic agent in a short period : report of two cases

Portal vein thrombosis (PVT) after splenectomy in a patient with portal hypertension occurs with unusually high frequency. Recently, two patients with PVT following splenectomy were treated by fibrinolytic therapy with an enormous dosage of urokinase (UK) in a short period. PVT was quickly dissolved without side effects and the patients are now doing well without any recurrence of PVT. Therefore, when there is no evidence of bowel infarction, fibrinolytic therapy with an enormous dosage of UK over a short period is deemed to be both effective and essential as a conservative therapy for PVT.

The role of endothelin in the pathophysiology of renal impairment during acute liver rejection.

We assessed the role of endothelin in the development of renal dysfunction during acute rejection by examining the effect of a selective endothelin A (ETA) receptor antagonist BQ-123 in rats with acute liver rejection. Serum endothelin levels and endogenous creatinine clearance (Ccr) were monitored on days 1, 3, 5, 7, and 9 postoperatively. As indicators of renal hemodynamics, the estimated hemoglobin concentration of renal tissue (IHb) and the oxygen saturation of hemoglobin in renal blood (ISO2) were determined by reflectance spectrophotometry. In addition, the clearance of inulin and p-aminohippurate were determined, and the renal tissue blood flow was estimated by laser-Doppler flowmetry (LDF). As a model of allograft rejection, Lewis rats were transplanted orthotopically with DA rat livers. The serum endothelin level of allografted rejectors was significantly (P<0.05) higher than that of isografted controls (Lewis rats with Lewis livers) on postoperative day 5, and it increased to a maximum of 5.38pm0.95 pg/ml on day 9 (versus 1.23pm0.18 pg/ml preoperatively). The values of Ccr, IHb, and ISO2 were all significantly (P<0.05) lower in allografted rejectors than in isografted controls on day 5, and subsequently declined to a minimum on day 9 (P<0.01). Treatment of allografted rejectors with BQ-123 markedly improved the renal parameters to levels similar to those in the isografted controls. These results strongly suggest that endogenous endothelin may play an important role in the development of renal impairment during acute liver rejection by reducing renal blood flow through binding with ETA receptor.

Hepatocellular carcinoma associated with lupoid hepatitis: A review of Japanese reports

A 66-year-old woman was diagnosed as having lupoid hepatitis due to the presence of hypergammaglobulinemia, lupus erythematosus cells, and positivity for antinuclear, anti-DNA, and anti-smooth muscle antibodies. None of the serum hepatitis B markers were positive. Symptomatic relief was obtained by prednisolone administration. Five years after the diagnosis of lupoid hepatitis, hepatocellular carcinoma (HCC) was detected by ultrasonography and computed tomography, after which hepatectomy was performed. Although transcatheter arterial embolization was done on two occasions and repeat hepatectomy was performed twice for recurrent HCC, her liver function remained good with the prednisolone treatment. Antibody for hepatitis C virus has been negative since our first check in 1992. As of this writing, the patient has been alive and well 6 years and 2 months after the first hepatectomy. There have been no previous reports of 6-year survival after hepatectomy for HCC associated with lupoid hepatitis.

Inflammatory pseudotumour-like follicular dendritic cell tumour of the spleen

We describe an unusual case of a 73-year-old woman presenting with a solitary splenic mass 8 cm in diameter and an elevation of serum soluble interleukin-2 receptor level. The preoperative diagnosis was primary malignant lymphoma of the spleen. Splenectomy was conducted. Histological analysis confirmed an inflammatory pseudotumour-like follicular dendritic cell tumour that showed different clinicopathological features from those of the classic follicular dendritic cell tumour. Only 33 cases of inflammatory pseudotumour-like follicular dendritic cell tumour have so far been reported. We discuss the incidence, presentation and management of this rare disease.

A Case of Colonic Perforation Complicated with Acute Pancreatitis.

急性膵炎における合併症として大腸穿孔をともなうことはまれである. われわれは急性膵炎が原因と考えられた横行結腸穿孔例を経験し手術によりこれを救命しえたので報告する. 症例は48歳の男性で, 発熱と全身倦怠感を認め検査のため入院となった. 腹部超音波検査, CT検査にて後腹膜膿瘍を疑い, 注腸造影検査を施行したところ横行結腸において腸管外への造影剤の漏出が認められたため, 後腹膜膿瘍および大腸穿孔と診断し緊急手術を行った. 開腹すると後腹膜は膨隆し切開にて多量の膿の排出を認め, 横行結腸に穿孔を認めた. 術式は横行結腸, 下行結腸切除と人工肛門造設ならびに後腹膜ドレナージを行った. 切除した大腸の穿孔部位の炎症所見は漿膜側において顕著で組織学的にpericolitisおよびmarginal arteryの血栓を認め, 急性膵炎による虚血性変化が大腸穿孔の原因と考えられた.

Advanced gastric carcinoma in an 18-year-old man: A case report

We report a case of advanced gastric adenocarcinoma (stage IVb) in an 18-year-old Japanese man who underwent extensive surgery followed by intensive adjuvant chemotherapy. We also review 12 cases of gastric carcinoma in teenagers, including this case. We found that gastric carcinoma in teenagers had the following characteristics similar to those found in older patients with the disease: 1) there was no sexual predominance (male: female=5:7) and no familial tendency; 2) epigastric pain was the most common symptom (58.3%, 7/12); 3) depressed tumors on macroscopic examination and undifferentiated adenocarcinoma on histologic examination were common (83.3%, [10/12] and 75%, [9/12], respectively); and 4) total gastrectomy was performed in more than half of the patients (7/12). In some cases, chemotherapy was effective for advanced disease, although there was no response in this case. Teenagers with persistent upper abdominal symptoms should undergo endoscopy for histologic diagnosis, because early diagnosis may be lifesaving.

Regulation of tight junction formation in intestinal epithelial cells by the IL-15 ligand-receptor system

Background: Human intestinal epithelial cells express IL-15 as well as IL-15 receptors consisting of the IL-15 receptor ct, IL-2 receptor 13 and 7c subunits. However the functional role of the IL-15 ligand receptor system in the regulation of intestinal epithelial cell function is unknown but may modulate the intestinal epithelial barrier. We assessed the regulation of protein levels and cellular distribution of the tight junction associated proteins ZO-1, ZO-2, and occludin in intestinal epithelial ceils by an IL-15 and IL-2 receptor 13 chain dependent pathway. Methods: The human intestinal epithelial cell line T-84, a model of intestinal crypt epithelium, which lacks the expression of the IL-2 receptor 13 chain constitutively but expresses IL-15, was stably transfected with the IL-2 receptor 13 chain to substitute a complete IL-15 receptor complex. Formation of tight junctions was determined by the measurment of transepithelial electrical resistance (TER). Expression of ZO-1, ZO-2, occludin, and E-cadherin as well as phosphotyrosine kinase activity was assessed by Western blotting of membrane and cytosol associated proteins. Cell proliferation was determined by 3H Thymidine uptake and MTS assays. Results: Expression of the IL-2 receptor 13 chain in T-84 cells resulted in a 3 fold increase of steady state TER within 4 four days after replating above the levels reached by the parental T-84 cells. The development TER in IL-2 receptor 13 chain transfected T-84 cells could be further enhanced by exogenous IL-15 and blocked by addition of anti IL-2 receptor antibodies. In contrast cell proliferation of IL-2 receptor 13 chain transfected and parental T-84 ceils was not altered. IL-2 receptor 13 chain transfected T-84 ceils demonstrated strong upregulation of tyrosine phosphorylation of a number of proteins with molecular masses of 120-100 and 60-40 kDa. The protein levels of ZO-1 and phosphorylated and unphosphorylated Occludin were increased 10 fold in the membrane associated protein fractions of IL-2 receptor 13 chain transfected T-84 cells compared to parental cells. In contrast, the levels of ZO-2 in membrane associated fractions of the stable transfectans was decreased 3 fold. The protein levels of E-cadherin were not regulated by the expression of the IL-2 receptor 13 chain in T-84 cells. Conclusion: Reconstition of a complete IL-15 receptor complex in T-84 cells results in autocrine regulation of the tight junction associated proteins ZO-1, ZO-2 and Occludin leading to the marked increase of TER. IL-15 may be an important regulator of intestinal epithelial cell barrier function.