Caveolae in mesangial cells and caveolin expression in mesangial proliferative glomerulonephritis.

BACKGROUND: Caveolae are plasma membrane invaginations that have a diameter of 40 to 60 nm. Recent evidences have demonstrated that caveolae contain a variety of signal transduction molecules. Caveolin is a marker protein of caveolae and has been proposed to play a negative regulatory role in signal transduction. The aim of this study was to investigate the behavior of caveolae and caveolin in experimental glomerulonephritis, the localization of both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) receptors in the caveolae membrane, and the regulation of caveolin expression in cultured mesangial cells. METHODS: The expression of caveolin-1 was examined by immunoblotting and immunohistology using anti-caveolin antibody in anti-Thy-1 nephritis. The caveolae membrane fraction of mesangial cells was isolated by sucrose gradient method and expression of PDGF receptor and TGF-beta receptor were detected by immunoblotting. The effects of mitogens such as phorbol 12-myristate 13-acetate (PMA) and PDGF on the expression of caveolin-1 protein and mRNA were also examined in cultured mesangial cells. RESULTS: Caveolin-1 was mainly expressed in glomeruli and was significantly up-regulated in anti-Thy-1 nephritis rat kidney. In cultured mesangial cells, the membrane invaginations of caveolae were revealed by electron microscopy. PDGF receptors abounded in the caveolae membrane and rapidly changed their subcellular distribution after ligand stimulation. In contrast, TGF-beta receptors abounded in the non-caveolae membrane and did not change after ligand stimulation. Decreases in caveolin-1 protein, which were associated with increases in mRNA expression after the exposure of PMA or PDGF-BB, suggested an increased turnover of caveolin-1 in mesangial cells stimulated by mitogens. CONCLUSION: To our knowledge, this electron microscopical study is the first to demonstrate the presence of caveolae in cultured mesangial cells. Caveolae integrate PDGF receptors, and caveolin-1 may play a role in the pathogenesis of the mesangial proliferative glomerular diseases through PDGF signaling.

Migrating site of bleeding in a right colon demonstrating angio-dysplasia following a segmental resection of the colon. A unique variant of angiodysplasia.

BACKGROUND/AIM: A case of angiodysplasia of the right colon presenting with a migrating site of bleeding following a segmental resection of the colon in a 38-year-old Japanese is herein reported. METHODS: The case records of a patient with severe intestinal bleeding and multiple surgeries were reviewed, and then the histologic features were compared with the operative findings. The patient received many units of packed red blood cells and had also undergone three segmental colectomies and most recently a curative ileocolostomy. Despite an exhaustive evaluation, the bleeding sites could not be detected clinically. RESULTS: Ectatic, tortuous submucosal veins were presented in four sections of the colon (cecum, ascending colon and transverse colon, respectively) out of a total of 30 sections that were examined. These veins pierced the proper muscle layer of the colon, but did not traverse the muscularis mucosa. Our case of segmental microscopic angiodysplasia may represent a previously unreported unique variant, because the angiodysplastic lesions were present in the segmental colon and they developed bleeding from the distal remnant colon immediately after each segmental colectomy until an extended right hemicolectomy containing the oral part of the descending colon was done. In spite of the severe bleeding, the mucosa of the colon appeared to be essentially normal during a macroscopic inspection. CONCLUSION: Gastrointestinal bleeding from angiodysplasia is generally assumed to arise from macroscopically visible vascular lesions within the mucosa. However, angiodysplastic lesions are often unrecognizable and multiple in the gastrointestinal tract, and especially tend to affect both the cecum and ascending colon. When this disease process is recognized, a subtotal colectomy may thus be called for to control bleeding.

Analyses of microsatellite instability and the transforming growth factor-beta receptor type II gene mutation in sporadic human gastrointestinal cancer.

Microsatellite instability (MSI) and transforming growth factor-beta receptor type II (RII) gene mutation have been reported in many types of tumors and their instance seem to vary among the tumors investigated. To determine the relation between MSI and RII gene mutation in sporadic gastrointestinal cancer development, 21 esophageal, 19 gastric, and 27 colorectal cancers were investigated. The presence of MSI was screened by single strand conformation polymorphism (SSCP) method using six microsatellite markers. RII gene mutations were detected by SSCP method and direct sequencing. MSI was detected in seven of 21 (33.3%) esophageal cancers, three of 19 (15.8%) gastric cancers and seven of 27 (25.9%) colorectal cancers. However, RII gene mutations were observed in only two of seven (28.6%) MSI-positive colorectal cancers. Our data suggest that among sporadic gastrointestinal cancers, colorectal cancers seem to be the most frequent target organ involved in carcinogenesis through RII gene mutation, which thus appears to be related to organ specificity.

Erythropoietin impairs endothelium-dependent vasorelaxation through cyclooxygenase-dependent mechanisms in humans.

Hypertension is a major complication of recombinant human erythropoietin therapy in patients with end-stage renal disease. Although the mechanisms for this pressor effect remain unknown, in vitro and ex vivo experiments suggest that erythropoietin stimulates release of cyclooxygenase-dependent endothelium-derived contracting factors (EDCFs) and attenuates endothelium-dependent vasorelaxation. To investigate the effect of erythropoietin on human endothelial function, we measured forearm blood flow by strain gauge plethysmography before and after intraarterial incremental administration of erythropoietin (10 to 300 IU/min, total 3000 U), while infusing acetylcholine (4 to 24 microg/min) and sodium nitroprusside (0.2 to 1.2 microg/min) in healthy male volunteers (n = 12). To examine a possible role of EDCFs, we repeated the same protocol under the pretreatment with oral indomethacin (50 mg), a cyclooxygenase inhibitor (n = 8). Infusion of erythropoietin into the brachial artery increased the erythropoietin blood concentration of venous effluents significantly (P < .0001) without changes in blood pressure and basal forearm blood flow. Acetylcholine and sodium nitroprusside increased forearm blood flow dose dependently before and after erythropoietin administration. However, acetylcholine-induced vasodilation (endothelium dependent) was significantly attenuated (P < .001) after erythropoietin administration, whereas vasodilation to sodium nitroprusside (endothelium independent) was unchanged. After indomethacin pretreatment, erythropoietin no longer attenuated endothelium-dependent vasorelaxation. Our results indicate that erythropoietin may impair endothelial function acutely, probably through cyclooxygenase-dependent EDCFs in humans. Long-term effects of erythropoietin on endothelial function in uremic patients remain to be elucidated.

Percutaneous transhepatic cholangioscopic lithotripsy and change of biliary manometry patterns.

BACKGROUND/AIMS: Percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) is used to remove bile duct stones. This work aims to evaluate the clinical usefulness of PTCSL and the reversibility of the terminal bile duct dysfunctions after PTCSL. METHODOLOGY: Thirty patients who underwent PTCSL using mechanical and/or electrohydraulic lithotripsy over the past 10 years (20 patients with common bile duct stones and 10 with intrahepatic bile duct stones) were evaluated. Terminal bile ductal pressure was measured using the percutaneous transhepatic biliary drainage (PTBD) tube prior to and after lithotripsy by means of variable-load cholangiomanometry. RESULTS: Complete stone extraction was possible in 26 patients (86.7%). The other 4 patients had intrahepatic stones. Complications included 2 cases of hemobilia, one of pneumonia, and 3 of localized peritonitis. Of 26 patients without residual stones, only 4 patients had a linear pressure flow (P-F) pattern which indicates normal biliary tract function prior to lithotripsy. In 17 of 22 patients with other type P-F patterns, however, these types also changed to a linear pattern after complete removal of stones. The P-F pattern of the other 5 patients remained unchanged. CONCLUSIONS: PTCSL is a safe and efficient method treating biliary tract lesions while preserving the function of the sphincter of Oddi. The terminal biliary tract function normalized after stone removal. Thus, PTCSL was useful for patients with complicated bile duct stones not accessible to endoscopic retrograde management.

Vascular reconstruction of the hepatic artery using the gastroepiploic artery: a case report.

A 59 year-old woman with obstructive jaundice secondary to proximal bile duct carcinoma underwent percutaneous transhepatic biliary drainage (PTDB). This revealed complete obstruction of the bifurcation of the hilar hepatic duct and encasement of the right hepatic artery. Wedged hilar hepatectomy with combined resection of the extrahepatic bile duct, gallbladder, and the encased right hepatic artery was performed. The hepatic artery was reconstructed using an in situ right gastroepiploic artery (GEA) pedicle graft. The anastomosis was protected with fatty tissue from the greater omentum. This technique can be used to reconstruct the hepatic artery after radical surgery for malignant hepatobiliary and pancreatic disease.

Extracorporeal bypass using a centrifugal pump during resection of malignant liver tumors.

BACKGROUND/AIMS: Total hepatic vascular exclusion (THVE) during extracorporeal bypass is used for hepatic resection in patients with malignant liver tumors. The aim of this study was to determine the efficacy of hepatectomy during total hepatic vascular exclusion using a centrifugal pump (Bio-pump). METHODOLOGY: Fourteen patients with malignant liver tumors who underwent hepatectomy during total hepatic vascular exclusion using the Bio-pump were studied retrospectively. RESULTS: In 3 of 14 patients, insufficient hepatic vascular exclusion was achieved. Six patients underwent tumor resection during total hepatic vascular exclusion, without extracorporeal bypass. In the remaining 5 patients, flow exclusion averaging 1500 ml was achieved with the Bio-pump, and hepatectomy was performed during the procedure. In these 5 patients, the mean operative time and blood loss were 11 hours 38 minutes and 6850 +/- 2451 ml. The Bio-pump bypass time, the excluded blood flow and the mean blood pressure were 82 minutes, 1650 ml and 108/53 mmHg, respectively. The arterial ketone body ratio (AKBR) decreased from a pre-operative value of 1.85-0.32 during total hepatic vascular exclusion. CONCLUSIONS: Total hepatic vascular exclusion was useful for hepatectomy in patients with tumor invasion into the hepatic vein and inferior vena cava, or tumor thrombus in the inferior vena cava and right atrium. However, this technique did not decrease blood loss or improve outcome in patients undergoing hepatectomy.

Microsatellite instability in double cancers of the esophagus and head and neck.

It is generally accepted that patients with squamous cancers of the esophagus are known to have a high risk of concomitant head and neck cancer. However, there have been only a few reports describing microsatellite instability (MSI) in patients with both esophageal squamous cell carcinoma and head and neck cancers. To evaluate the role of genetic instability in carcinogenesis in such patients, we analyzed six microsatellite loci in 21 tumors from 10 patients who had developed primary cancers of both the esophagus and the head and neck. MSI was detected in 6 out of 10 patients. In five patients with double cancer, MSI was observed at the same microsatellite loci in both the esophageal and the head and neck tumors obtained from the same individuals. These data suggest that such patients may have the same underlying defect in the mismatch repair system, providing insight into possible mechanisms for field carcinogenesis.

Radiation-associated rectal cancer: report of four cases.

BACKGROUND/AIMS: Radiation-associated rectal cancer is a remarkable clinical entity. We demonstrate 4 patients (mean age 68 years, range 63-74) who had undergone pelvic radiotherapy for cervical cancer. We indicate some characteristics of radiation-associated rectal cancer. RESULTS: Two patients had received intracavitary and external pelvic radiotherapy, while the remaining 2 had external pelvic radiotherapy following hysterectomy. The mean total radiation dose was 63 Gy, though radiation dose information was not available for 1 patient. Colorectal cancer developed at a mean time of 20.7 years (range 11-30) after radiation therapy. All patients presented with chronic radiation colitis, and 3 demonstrated abnormal tumor markers. Colonoscopy revealed an ulcerative, localized well-differentiated adenocarcinoma of the rectosigmoid colon in 1 patient, and diffusely infiltrating cancers of the lower rectum, one signet-ring cell carcinoma and two mucinous carcinomas in the remaining 3. One case was stage I, 2 were stage IIIa, and the remaining case was stage IV. Three patients underwent abdominoperineal resection. The remaining patient was felt to be inoperable. The colorectal wall demonstrated the changes of chronic radiation injury. Two patients died within a short time because of their advanced cancers. CONCLUSION: Radiation-associated rectal cancer has a tendency to be diagnosed in the advanced stage and to have a poor prognosis. A literature review and our case report suggest that since there are no reliable clinical or laboratory indicators of the presence of a curable colorectal cancer in the setting of chronic radiation proctocolitis, surveillance with a colonoscope should be done 10 years after irradiation in patients with previous pelvic radiotherapy.

Surgical treatment for proximal bile duct carcinoma.

BACKGROUND: The surgical management of proximal bile duct carcinoma is controversial. There is no consensus among surgeons as to the indications for radical resection. This article described personal experience with the different surgical procedures for patients with proximal bile duct carcinoma. METHODS: The medical records of fifty-two consecutive patients undergoing surgical resection over a 20-year period were retrospectively analysed in terms of pathology, perioperative mortality, clinical course, and overall survival. RESULTS: The 1-, 3- and 5-year survivals for the entire group were 63.3%, 24.5%, and 21.0%, respectively. The results for local resection of the extrahepatic bile duct in 35 cases were unsatisfactory. Radical resection that included the right extended hepatic lobe, caudate lobe, and extrahepatic bile duct was performed in 9 patients and demonstrated an excellent 5 year survival rate of 44.4%. However, hospital mortality was 22.2%. There was no significant difference among the operative procedures for patients with advanced disease. CONCLUSION: Radical resection remains the procedure of choice in proximal bile duct carcinoma. However, results with surgical therapy alone remain unsatisfactory. Multimodality treatment that also includes radiotherapy and/or chemotherapy is recommended.

Morphologic and mucin histochemical analysis of transitional zones in advanced ulcerated colorectal carcinomas: potential prognostic indicators.

BACKGROUND AND OBJECTIVES: The transitional zone, which is normal-appearing mucosa that surrounds a primary colorectal carcinoma, has characteristic histologic features, and an increased amount of sialomucin in the transitional zone have been associated with a poorer prognosis. To clarify the prognostic effects of changes in the transitional zone we studied the transitional zone in cancers of the colon and rectum. METHODS: A total of 105 specimens resected for advanced colorectal carcinoma were studied to identify the effectiveness of evaluating morphologic types (polypoid or nonpolypoid growth type) and mucin expression (sulfomucin or sialomucin type) of the transitional zone as a prognostic indicator. RESULTS AND CONCLUSIONS: Nonpolypoid carcinomas were likely to have invaded the deeper layers and lymphatic vessels and go on to develop advanced disease. Sulfomucin-type tumors were predominantly found in the right side colon and followed a relatively favorable course. Our results indicate that the morphologic and mucin components of the transitional zone may be prognostic indicators for advanced colorectal carcinoma.

Large synovial cyst of the pelvis containing rice bodies. A case report.

Although synovial pelvic cysts are very uncommon they enter into the differential diagnosis of presacral and ovarian cysts. In the elderly male whom we report, a large cyst arose from the hip and extended during a five year period to involve the entire pelvic cavity. The cyst, which contained a large number of "rice bodies" was excised surgically.

Esophageal cancer in patients with head and neck cancers.

Nine male patients with separate primary cancers of the esophagus and head and neck (pharynx, larynx) presented with a mean age of 56 years (41-69). They included 7 pharyngeal cancer patients and 2 laryngeal ones. Esophageal cancer was discovered synchronously in 6 patients and metachronously in 3 (1, 4, and 11 years later, respectively). The head and neck cancer was stage-I in one patient, stage-II in 4 and stage-IV in 4. The esophageal cancer was cervical in 2, thoracic in 6 and abdominal in 1. It was early cancer (stage-0) in 6 patients and advanced (stage-IV) in 3. The esophageal cancer was more advanced in the metachronous group, while it was early in the synchronous group. Since the head and neck cancer was advanced, all patients underwent a total laryngectomy for their head and neck cancers. As for esophageal surgery, a transhiatal esophagectomy was, in principle, performed for early cancers while a total thoracic esophagectomy was done for advanced cancers. For the reconstruction of the esophagus, a gastric tube was used. Four patients are still alive with a mean survival time of 25 months, whereas five died of cancer recurrence of either type a mean of 19 months after surgery. As compared with the survival rates of the patients with esophageal cancer alone, the 5-year survival rate was 18.2% for patients with double cancers in this series and 27.9% for those with esophageal cancer alone.

The use of intraoperative ultrasonography for detecting tumor extension in bile duct carcinoma.

UNLABELLED: The purpose of this study was to investigate the clinical feasibility of using intraoperative ultrasonography (IOUS) to detect tumor extension in bile duct carcinoma, especially longitudinal invasion along the bile ducts into either the hepatic parenchyma or adjacent hilar vessels. MATERIALS AND METHODS: The medical records of 14 patients with bile duct carcinoma who underwent surgical treatment at the First Department of Surgery, University of the Ryukyus, were retrospectively analyzed. All patients were examined by IOUS during the operation. The resected specimens were processed in order to compare the ultrasound images with the histological findings. RESULTS: The echo level of the primary lesion was not consistent. Specific echo patterns, such as a thickening of the echogenic layer (TEL) adjacent to the main tumor showing cancerous invasion, were observed in ten patients, 71.4% (nodular invasive 7, invasive 3) which were later confirmed by microscopic examinations and ultrasonic findings. The detection rate of TEL was 87.5% in nodular invasive type and 100% in invasive type, respectively. The TEL histologically coincided with a layer of fibrotic hypertrophy around the infiltrating tumor cells. The intramural invasion beyond the edge of TEL was detected in only 2 out of 11 patients. The accurate detection rate of the involvement of the portal vein and the hepatic artery by IOUS was 83.3% and 60%, respectively. Based on the above findings, IOUS is thus considered to be essential for evaluating tumor extension along the bile ducts, and also greatly helps in selection of the most appropriate operative procedure, especially in hilar cholangiocarcinoma.

Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension.

NG,NG-dimethyl-L-arginine (ADMA) is an endogenously synthesized nitric oxide (NO) synthase inhibitor which has potent pressor/vasoconstrictor effects. Dimethylargininase metabolizes ADMA to L-citrulline and plays a key role in determining the in vivo levels of ADMA. To investigate the role of ADMA in the pathogenesis of hypertension, we measured 24-hour urinary excretion of ADMA (UADMA) and nitrate/nitrite (NOx) in Dahl salt-sensitive hypertensive rats and spontaneously hypertensive rats (SHR). In Dahl salt-resistant rats, high-salt diet (8% NaCl) did not increase blood pressure and increased urinary NOx (P < .01) without changes in UADMA compared with low-salt diet (0.3% NaCl). In contrast, in Dahl salt-sensitive rats, high-salt diet increased blood pressure (P < .01), did not change urinary NOx excretion, and increased UADMA (P < .01). There was a significant (r = .65, P < .01) correlation between UADMA and the level of blood pressure in Dahl salt-sensitive rats. Plasma levels of NOx and ADMA and renal dimethylargininase content were comparable among them. These results may suggest that in Dahl salt-resistant rats, blood pressure is kept constant during high-salt intake, possibly due to the compensatory increased production of NO, and that in Dahl salt-sensitive rats, high-salt intake increases the production of ADMA, attenuates the compensatory increases in NO, and increases blood pressure. These results also suggest that the systemic production of ADMA is not dependent on renal dimethylargininase. SHR had significantly greater urinary NOx excretion (P < .05) and smaller UADMA than Wistar-Kyoto rats (P < .05), and UADMA was inversely correlated with their mean arterial pressure (r =.64, P < .05). In conclusion. ADMA, independently of the renal dimethylargininase content, may play a role in the pathogenesis in Dahl salt-sensitive hypertensive rats but not in SHR.

Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans.

BACKGROUND: Although long-term lipid-lowering therapy improves endothelium-dependent vasodilatation in humans, it remains unknown whether the short-term removal of LDL per se ameliorates endothelial dysfunction. METHODS AND RESULTS: To examine the effects of a single session of LDL apheresis on endothelial function in patients with hypercholesterolemia, we measured forearm blood flow (FBF) by strain-gauge plethysmography before and after single LDL apheresis while infusing acetylcholine (ACh; 4 to 24 micrograms/min) and sodium nitroprusside (SNP; 0.2 to 1.2 micrograms/min). The single session of LDL apheresis reduced total LDL (from 142.2 +/- 15.0 to 32.6 +/- 5.0 mg/mL, P < .0005) and oxidized LDL (from 111.6 +/- 22.8 to 30.0 +/- 5.4 ng/mL, P < .005). Although ACh and SNP increased FBF dose-dependently before and after LDL apheresis, the endothelium-dependent vasodilatation responses to ACh were significantly augmented (P < .01) after the single session of LDL apheresis without changes in the endothelium-independent vasodilatation responses to SNP. The plasma levels of total and oxidized LDL correlated with the degree of ACh-induced vasodilatation. Furthermore, the local production of nitrate/nitrite, metabolites of NO, during ACh infusion was significantly (P < .05) augmented by LDL apheresis, and there was a significant correlation between the degree of ACh-induced vasodilatation and the production in nitrate/nitrite (r = .99, P < .0005). CONCLUSIONS: We demonstrated that even a single session of LDL apheresis with the reduction of total LDL and oxidized LDL improved endothelial function. Our results suggest that total LDL and/or oxidized LDL may directly impair endothelial function in the human forearm vessel.

Plexiform leiomyoma of the esophagus: a peculiar gross variant simulating plexiform neurofibroma.

A plexiform variant of leiomyoma of the esophagus in a 51-year-old woman is reported. The patient was diagnosed with a tumor of the esophagus in an X-ray mass survey of the upper gastrointestinal tract. She was referred to the Ryukyu University Hospital for further examination. She appeared healthy with no complaints. Upper gastrointestinal series revealed an oval, well-defined filling defect in the lower esophagus just above the esophagogastric junction. Endoscopy revealed an undulating bulge covered with normal esophageal mucosa. Endoscopic ultrasonography showed a sharply demarcated hypoechoic mural tumor with internal linear pattern, with no evidence of penetration into the surrounding tissue. These findings were evaluated as consistent with a leiomyoma. Removing the tumor by enucleation was easily accomplished. Unexpectedly, on gross inspection, the tumor was a plexiform type, mimicking a plexiform neurofibroma. Light and electron microscopic examination and immunohistochemistry of the tumor tissue confirmed leiomyoma. Since the enucleation of the tumor, the patient has been free of recurrence and symptoms for 1.5 years at the time of this report.

[A case of anti-glomerular basement membrane antibody (AGBMA) nephritis associated with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)].

A 68-year-old patient visited our hospital, because of progressive renal failure. Laboratory data were serum creatinine 13.3 mg/dl, BUN 74.3 mg/dl, AGBMA 134U, MPO-ANCA 37% and CIC 1.6 g/dl. Hemodialysis was performed on admission and renal biopsy was conducted. Though the histological findings showed fibrocellular crescents and global sclerosis in many glomeruli, renal function was gradually ameliorated by administration of prednisolone (40 mg/day) and cyclophosphamide (50 mg/day). After 3 weeks of therapy, hemodialysis was withdrawn temporarily. Because of the complication of pneumocystis carini, prednisolone and cyclophosphamide were discontinued, and maintenance hemodialysis was resumed. In spite of progressed histological findings, hemodialysis was withdrawn at least temporarily through the use of pharmacological therapy. Thus, the presence of ANCA may indicate a relatively good prognosis of AGBMA nephritis.