The ultrastructure of parapapillary chorioretinal atrophy in eyes with secondary angle closure glaucoma

Background: The present study was performed to investigate the ultrastructure of deep retinal layers and choroid corresponding to the parapapillary chorioretinal atrophy in eyes with secondary angle-closure glaucoma. Methods: The glaucomatous eyes included two eyes enucleated due to iris ring melanoma with high intraocular pressure and one eye with neovascular glaucoma enucleated due to ocular pain. The control eyes included one eye enucleated due to choroidal malignant melanoma with normal intraocular pressure and one eye enucleated during surgery for supramandibular carcinoma. These eyes were studied with light and electron microscopy. Results: In the region of parapapillary chorioretinal atrophy of glaucomatous eyes, the retinal pigment epithelial cells showed degenerative changes, such as loss of basal in foldings and microvilli, degenerated mitochondria, vacuolar degeneration and irregular distribution of melanin granules. The photoreceptors were decreased in number in this area of glaucomatous eyes. The lumen of the choriocapillary vessels adjacent to the optic nerve was collapsed. Conclusion: These results elucidate the fine structures of deep retina and choroid in the region of parapapillary chorioretinal atrophy of glaucomatous eyes, and suggest that the reduced choroidal perfusion might be the pathogenetic mechanism of glaucomatous parapapillary chorioretinal atrophy.     

Physical dependence liability test of ifenprodil in rats (author's transl)

A single administration of ifenprodil at the doses of 100, 200 and 400 mg/kg (p.o.), and 50 and 100 mg/kg (i.m.) produced a moderate CNS depression in rats, such as, sedation, ptosis, systemic muscle relaxation and decrease in motor activity. These symptoms appeared dose-dependently and persisted for about 4 hours following administration. In a direct physical dependence test, 5 groups of rats were fed the ifenprodil-admixed food together with drinking water ad libitum for 24 hours daily for 53 approximately 103 days (mean ifenprodil intake, 43--240 mg/kg/day), on the gradedly increased dosage schedule with a dosage level of 0.5 vs. 1 mg/g food to 4 mg/g food. In the natural withdrawal following administration, no significant withdrawal signs were observed in any group. In a substitution test either for phenobarbital or morphine, no suppression of withdrawal signs during the period of cross-administration of ifenprodil and no maintenance of dependence were observed. In a physical dependence-producing test, the rats fed ifenprodil never manifested withdrawal signs such as diarrhea, "wet shakes", sudden loss of body weight as in the levallorphan precipitation test. Ifenprodil apparently has no physical dependence liability.     

Modulation of BUdR labeling index in rat brain tumors following intracarotid ACNU administration

Summary Chloroethy1nitrosourea (CENU) chemotherapy has yielded limited benefit on survival of malignant brain tumors. Intracarotid administration of CENU is expected to have the advantage of increasing drug concentration reaching tumors. To understand basic knowledge of intracarotid chemotherapy, we monitor changes of proliferating rate after intracarotid injection of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2chloroethyl)-3-nitrosourea hydrochloride (ACNU), using a bromodeoxyuridine (BUdR) labeling index (LI) in transplanted brain tumors of three cell strains.C6-2 tumor cells were in vitro sensitive to ACNU, and C6-2/ACNU and C6-1 cells were resistant. The drug sensitivity to ACNU was as follows: 11.9 tM in the C6-2 cells, 46.0 M in the C6-2/ACNU cells, and 49.7 M in the C6-1 cells at SD10, which gives 10% survival of clonogenic cells. The intracarotid ACNU at a dose of 30 mg/kg abruptly decreased the LI to 11% (mean) from 36% in C6-2 transplanted tumors. The LI remained low between 12 and 48 hours after, and then increased to the pretreatment level by 96 hours. In contrast, the LI of C6-1 tumors transiently fell to 15% from 42% at 12 hours after the injection, and subsequently increased to 36% at 24 hours and 37% at 48 hours.These results indicate that intracarotid ACNU administration shortly suppresses proliferating activity of tumors and that combined and alternating chemotherapy are mandatory for enhancing effectiveness of brain tumor chemotherapy.     

Acute toxicity,percutaneous absorption and effects on hepatic mixed function oxidase activities of 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Irgasan® DP300) and its chlorinated derivatives

Acute toxicity of 2,4,4-trichloro-2-hydroxydiphenyl ether (Irgasan^® DP300) (I) and its three chlorinated derivatives, 2,3,4,4-tetrachloro-2-hydroxydiphenyl ether (II), 2,4,4,5-tetrachloro-2-hydroxydiphenyl ether (III) and 2,3,4,4,5-pentachloro-2-hydroxydiphenyl ether (IV), in mice were examined by intraperitoneal injection. The LD₅₀ values of Irgasan DP300, II, III and IV were 1,090, 710, 650 and 430 mg/kg, respectively.The percutaneous absorptions of these tritiated compounds were also examined by the application on the backs of mice. The radioactivities in most tissues reached to the maximal levels at 12 h or 18 h after dosing, which corresponded to 11–76% of the maximal levels given by the oral administration (Kanetoshi et al. 1988a). These results show the high percutaneous absorbability of Irgasan DP300 and its chlorinated derivatives.The intraperitoneal administrations of III and IV to rats induced hepatic microsomal aminopyrine N-demethylase and aniline 4-hydroxylase activities similarly to phenobarbital. These chlorinated derivatives also increased cytochrome P-450 content, and the activities of aminopyrine N-demethylase and N-methylaniline N-demethylase in hepatic microsomes from mice. The extents of the increases were similar to those by phenobarbital and 3-methylcholanthrene.     

Coagula tamponade as a complication of open heart surgery: the clinical significance and diagnostic value of transesophageal echocardiography]

The pathogenesis of low cardiac output failure (LOF) immediately after open heart surgery was studied in 41 patients with LOF and 15 control patients without LOF using echocardiography. In 35 patients, transesophageal echocardiography was also performed. Left ventricular (LV) contraction was impaired in 28 of the 41 LOF patients, in whom LV fractional shortening was less than 25%. In the other 13 LOF patients, however, it was greater than 25%. In 12 of these 13 patients, transesophageal echocardiography revealed that accumulating pericardial coagula were localized in the right side of the heart, deforming the right atrial and ventricular chambers. The LV end-diastolic diameter was significantly less than the control, indicating that the pericardial coagula disrupted the distension of the heart. Emergent coagulotomy was performed in 5 patients, and hemodynamic conditions were improved. In spite of "cardiac tamponade", the wall motion and pressure tracings of the right atrium and right ventricle in these patients differed from those in fluid tamponade. Therefore, this condition should be designated "coagula tamponade." In the other 22 patients in whom transesophageal echocardiography was employed, no coagula were observed. Since pericardial coagula can hardly be detected by transthoracic echocardiography, transesophageal echocardiography is indispensable for diagnosing pericardial coagula noted immediately after open heart surgery.     

Transient enlargement and spontaneous regression of interhemispheric cysts--a case report

We report a 5-year-old male patient with interhemispheric cysts which showed spontaneous reduction in size. The patient was consulted to our hospital at 2 days of life for the evaluation of intracranial cysts found by fetal ultrasonography. Magnetic resonance imaging (MRI) on admission disclosed multiple cysts in the interhemispheric region and agenesis of the corpus callosum. MRI performed later disclosed the association of pachygyria and heterotopia. On follow-up MRIs, the cysts peaked in size at 5 month of age and gradually reduced thereafter. He showed transient hypertonia but had neither neurological deficits nor signs of increased intracranial pressure except transient hypertonia throughout the course. The present case is the first with interhemispheric cysts showing spontaneous reduction in size. While the present case suggested that an interhemispheric cyst dose not necessarily need a surgical treatment, and that it is difficult to determine surgical indication based on clinical manifestations.     

Curative Resection of Microgastrinomas Based on the Intraoperative Secretin Test

The intravenous secretin injection test (secretin test) has been used for the differential diagnosis of gastrinoma. In this study we report that the intraoperative secretin test (IOS test) is also useful for determining the extent of curability in patients with Zollinger-Ellison syndrome (ZES). Twelve patients with ZES underwent surgical exploration and the IOS test. The results of the IOS test were obtained by rapid radioimmunoassay of the serum gastrin level (IRG) within 60 minutes. The test was diagnosed as negative when the maximum increase of serum IRG was less than 80 pg/ml and also less than 20% of the basal serum IRG level. Three of the twelve patients underwent pancreatoduodenectomy (PD), and two patients underwent distal pancreatectomy. Extirpation of duodenal tumors with dissection of regional lymph nodes was performed in seven patients. In two of the seven patients the IOS test remained positive after extirpation of the duodenal tumors and the dissection of regional lymph nodes. In one patient PD was performed on the basis of the positive results, and the IOS test became negative after PD. In the other patient, two tiny metastatic liver tumors were identified and were resected, but the IOS test did not become negative. We closed the abdomen in 11 patients when we obtained negative results from the IOS test. The results of the IOS test were almost identical to the data obtained by the standard assay postoperatively. The serum IRG levels of all but one patient fell to the normal level, and the secretin test became negative postoperatively. The IOS test is thus useful and indispensable for curative resection of microgastrinomas in patients with ZES.     

An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker.

We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin alpha2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin alpha2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin alpha2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin alpha2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin alpha2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.     

Long-term survival after radical resection of advanced pancreatic cancer

A 65-yr-old man who underwent pancreaticoduodenectomy with portal vein resection for pancreatic cancer is alive 8 yr after surgery. Originally, computed tomography (CT) revealed an 8-cm tumor in the pancreatic head. The tumor had infiltrated the portal vein, but grew expansively, so there was neither biliary obstruction nor jaundice. Pancreaticoduodenectomy with resection of the portal vein was performed for pancreatic cancer. Many tumor-infiltrating lymphocytes were seen within cancer cell nests on routine histopathology. We performed immunostaining for CD8, and found that a large number of the lymphocytes were CD8⁺ T cells. The patient’s prognosis was considered poor because the tumor was large and had infiltrated the portal vein. We suspect that long-term survival may be related to the response of CD8⁺ T cells to the cancer.     

Isoflavone aglycone-rich extract without soy protein attenuates atherosclerosis development in cholesterol-fed rabbits

The antiatherogenic effect of soy protein with intact isoflavones is well established, but the effects of isoflavones without soy protein have not been determined. We investigated the antiatherogenic effect of an isoflavone aglycone-rich extract (containing 429.4 mg/g isoflavone aglycones) without soy protein from fermented soy in cholesterol-fed rabbits. We fed 12-wk-old New Zealand white male rabbits diets containing 1 g/100 g cholesterol with 0, 0.33 or 1 g/100 g isoflavone aglycones for 8 wk. We also fed the rabbits a diet containing 1 g/100 g cholesterol with 1.09 g/100 g soy saponin-rich extract, a component other than isoflavone aglycones in the isoflavone aglycone-rich extract. Controls did not consume cholesterol, isoflavone aglycones or saponins. The isoflavone aglycone- and saponin-rich extracts did not affect the serum lipid profile of cholesterol-fed rabbits. The serum concentration of daidzein in its conjugated form was significantly higher in the high isoflavone group than in the low isoflavone group. The level of cholesteryl ester hydroperoxide (ChE-OOH) induced by CuSO(4) in plasma in the high isoflavone group was significantly less than that in the cholesterol group, and the ChE-OOH levels of LDL in the low and high isoflavone groups were significantly less than those in the cholesterol group. The ChE-OOH levels in plasma and LDL in the saponin group did not differ from the cholesterol group. In the aortic arch, the cholesterol concentration was significantly lower in the high isoflavone group, and malondialdehyde concentration was significantly lower in the low and high isoflavone groups compared with the cholesterol group; however these concentrations in the saponin group did not differ from those in the cholesterol group. The atherosclerotic lesion area of the aortic arch was significantly lower in the isoflavone groups (26.3% lower in the low isoflavone group and 36.9% lower in the high isoflavone group) than in the cholesterol group. The lesion areas were not different in the soy saponin and cholesterol groups. Immunohistochemical analysis revealed fewer oxidized LDL-positive macrophage-derived foam cells in atherosclerotic lesions in the aortic arch of isoflavone groups compared with that of the cholesterol group. These results suggest that the antioxidative action of isoflavones and their antioxidative metabolites inhibit the oxidation of LDL, thereby exerting an antiatherosclerotic effect.