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This study was undertaken to clarify whether the osteoid forming activity seen in osteosarcoma can be used as an index to show the degree of differentiation of the tumor. Twenty six human osteosarcomas which had been amputated in our clinics were used in this study. The whole slice of the primary tumor was stained by HE and Masson stain. The following observations were microscopically made in the peripheral, transitional and central part of the tumor; 1) the content and maturity of osteoid, 2) the degree of polymorphism and mitotic activity of the tumor cells. In 13 out of 26 cases, the amount and maturity of osteoid gradually increased toward the center of the tumor. On the other hand, the degree of polymorphism and mitotic activity of tumor cells in these cases gradually decreased toward the center. Mitotic activity in the center of the tumor decreased to about half of the peripheral part. The clinical courses of these 13 cases were milder than those in which the gradual increase of the amount and maturity of osteoid toward the center of the tumor were not observed. These results showed that zone formation of osteoid maturity in osteosarcoma can be used as an index to show the degree of differentiation of the tumor.

The primary site of the metastasis of osteosarcoma is the lung. More than 90% of patients have died of pulmonary metastasis in one to two years. Control of osteosarcoma depend upon the prevention of its pulmonary metastasis. The introduction of chemotherapy consisting mainly of Adriamycin, high-dose methotrexate with Leucovorin rescue and Cisplatinum, dramatically improved the prognosis of osteosarcoma. In the past, when systemic chemotherapy was not available, the five-year survival rate was around 19%. In patients who receive chemotherapy with the current combination of chemotherapeutic agents (ADM, HD-MTX, VCR, CPM, CDDP), the incidence of pulmonary metastasis was low, and the five-year survival rate increased to 65%. In patients who receive chemotherapy, pulmonary metastasis may be either delayed, with a single metastasis appearing after termination of treatment (late isolated type), or early and multiple, emerging in reaction to treatment (early multiple type). It is generally accepted that post-operative chemotherapy can inhibit pulmonary micro metastasis and prove to be of great significance in improving the survival rate of patients with osteosarcoma of extremities and achieve limb salvage operation. On the other hand, effective control of the side effects of drug administration such as nausea, vomiting, alopecia, cardio (ADM) and renal (CDDP) toxicity and bone marrow suppression, is a problem that must be solved as soon as possible.

In the present study, the anti-edema effect of AVS [1,2-bis (nicotineamide)-propane] was evaluated using the cat MCA occlusion model with or without recirculation. In the prolonged ischemia (PI) group, cortical edema as assessed by the changes in specific gravity, developed in those cortical areas where the mean 1-CBF was less than 25-30 ml/100 g/min during MCA occlusion (4 hours). In the recirculation group (2 hours' ischemia followed by 2 hours' recirculation: RC group), the ischemic threshold for edema development was almost the same as in the PI group. In both groups, the drop in cortical specific gravity was significantly suppressed by AVS. Regarding the time-course of 1-CBF, there was no difference between the PI-AVS-treated and PI-saline-treated groups. In the RC group, however, the postischemic hypoperfusion was significantly ameliorated by AVS. Based on the present and previous data showing the antiedema effect of AVS, the mechanism of action of AVS was discussed in relation to the pathomechanism underlying ischemic brain edema. Our new concept of ischemic brain edema is briefly stated below. Related in vitro studies have shown the followings: (i) the influx of sodium not of proteins is the principal cause of ischemic brain edema: (ii) the eicosanoid synthetic capacity of the brain microvessel (MV) is increased simultaneous to edema development (iii) an elevation in the level of hydroperoxides enhances the activities of Na+, K+-ATPase as well as the arachidonate cascade of MV. These data suggest that free fatty acids and free radicals liberated following cerebral ischemia stimulate the activity of the MV-Na+, K+-ATPase, which results in increased sodium influx across the BBB. AVS was shown to scavenge hydroxyl radicals and to inhibit the stimulatory effects of a lipid hydroperoxide (15-HPAA) on the activities of Na+, K+-ATPase and the arachidonate cascade of the MV. These actions of AVS may be linked to its antiedema effect.

A case of multiple aneurysm of superior mesenteric artery (SMA) branch is presented. A 54-year-old man with sudden onset of back pain was admitted to our hospital. Severe abdominal pain was developed and he fell into shock. Selective angiography of the SMA demonstrated aneurysm of the accessory middle colic artery to splenic flexure. Laparotomy disclosed much intraperitoneal blood and a large clot under the pancreatic body with a gushing hemorrhage. The bleeding vessel was ligated and sutured. The postoperative course was uneventful, but the subsequent angiography revealed another aneurysm of SMA branch, which was not able to be seen in the previous angiography because of overlapping with main SMA trunk. Resection of the aneurysm was done. The etiology of the latter aneurysm was suggested to be medial degeneration histologically. Fourty-nine cases of SMA aneurysm from the Japanese literature were reviewed and discussed. Emphasis is placed on early diagnostic laparotomy for appropriate management and the role of angiography in confirmation of bleeding site in case of spontaneous intraabdominal hemorrhage.

Werner's syndrome, a relatively rare and autosomal recessive disorder, is well known to be characterized by a high frequency of malignant neoplasm. The occurrence of familial neoplasm in patients with this condition, however, has been recorded only once before in the literature. Reported are the findings with regard to the occurrence of sarcomas in three siblings with Werner's syndrome. Two of the current three cases were of malignant fibrous histiocytomas, one in a 36-year-old man and one in a 32-year-old woman. The other case was of a leiomyosarcoma in a 26-year-old man. Two of the patients died of the tumors, although the third is still alive. The exact cause of the high incidence of malignant tumor in this family remains unknown, as is still so in other cases of Werner's syndrome.

Hind legs of dogs were amputated at the middle of the thigh and preserved in three different conditions: in ice water, in a refrigerator, and at room temperature. After 6 or 12 hours of ischemia, recirculation was established. The survival rate of the animals was observed and measurement of limb edema, potassium, pH, and lactate in the blood was performed to study the effects of hypothermia on prevention of "replantation toxemia." Cooling of the amputated limb was effective for prevention of toxemia, and the cooling effect was greater in ice water than in a refrigerator. However, when cooled in ice water, some animals died due to toxemia when the time of ischemia was prolonged to 12 hours. In the dead animals, a close relationship was observed between the developement of toxemia and metabolic acidosis due to the increase in lactate.

The sequential and histologic changes occurring in muscles from ischemia were investigated in dogs. The left hind limbs were amputated, and recirculation was established after preserving them either in ice water or at room temperature for six to 12 hours. Slight leakage of the muscle enzymes creatine phosphokinase (CPK), mitochondrial glutamic oxaloacetic transaminase (GOT-m), and lactate dehydrogenase (LDH) into the recirculated venous blood occurred in specimens preserved in ice water for six hours, but there was a marked increase in enzyme leakage in the other groups. Histologic muscle changes consisted of cell swelling and separation of the sarcoplasm from the endomysium. Electron microscopy revealed widening of the myofibrillar spaces, a virtual absence of glycogen granules, and degeneration of mitochondria. These results support the clinical practice that the amputated extremities must be preserved in ice water and that blood recirculation should be initiated within six hours of amputation.

A survey on literature reports and our own experimental studies on the pathogenetic mechanisms underlying ischaemic brain oedema is given and a new concept proposed. In regional incomplete ischaemia the lipoxygenase activity is enhanced, presumably caused by an increase of free radicals and hydroperoxides, leading to an enhancement of endothelial Na+, K+-AtPase and increased sodium and water transport from blood to brain. The aggravation of brain oedema and post-ischaemic hypoperfusion following recirculation appears to be mainly due to an activation of the cyclo-oxygenase pathway with release of oxidants from PGG2, which causes non-specific but detrimental damage to the endothelial and parenchymal cells. This new concept may open future perspectives in treatment which are briefly discussed.

In this study we reviewed cases of osteosarcoma, malignant lymphoma of bone and Ewing's sarcoma. Historically, osteosarcoma was unresponsive to chemotherapy. Most patients were treated by radiation or amputation alone and 80% of them died from pulmonary metastasis within 2 years. Five-year survival rate was 13%. Introduction of ADM, HD-MTX and CDDP improved dramatically the prognosis of these cases. Five-year survival rate was 60%. On the other hand, 11 cases of malignant lymphoma of bone and 4 cases of Ewing's sarcoma were treated by radiation with no local recurrence. VEPA or CHOP chemotherapy was used for the former with a five-year survival rate of 45%. For the latter, T-11 protocol (Rosen) was applied, and all patients survive with no metastasis. Other organ injuries circulatory disturbance, bone necrosis and growth-disturbance of bone in radiotherapy, myocardiopathy caused by ADM and renal toxicity of CDDP are all problematic.

Viral retinochoroiditis was induced experimentally by inoculation of herpes simplex virus into the vitreous body in rabbits. The animals were sensitized systemically using 2 pathogens as antigens (herpes simplex virus and toxoplasma gondii) 3 weeks prior to intraocular inoculation. Serum and intraocular fluid were collected 2 weeks after inoculation. The intraocular fluid antibody titers and quotients for these 2 pathogens were then measured to determine the effects of serum antibodies, which are thought to enter the eyes as a result of destruction of the blood-ocular barrier. Experimental criteria for antibody quotients were also determined. Antibody quotients for the etiological virus (herpes simplex virus) ranged from 2 to 20, with an average of 9.7. Those for toxoplasma gondii, the antibody of which is thought to enter the eye from the blood, were all less than 5 with average of 1.9. From these results, it would seem that when the antibody quotient of a pathogen in more than 6 in the intraocular fluid, it is likely to be an etiological organism, while the possibility of infection is very low when the quotient is under 2. More precise studies are required to identify an etiological pathogen when the quotient is 2-6.

To investigate the role played by immunoglobulins in the display of idiotope-like determinants by T cells, we investigated whether T cells transferred to congenically athymic mice would display the idiotypes of the nude host or of the T cell donor Igh genotype. 4-Hydroxy-3-nitrophenyl hapten (NP)-specific first-order suppressor T cells (Ts1) from Ighb-bearing mice display the NPb idiotype. Mature peripheral T cells from Igh congenic mice were used for reconstitution of nude mice in acute transfers. Before analyzing the idiotypic properties of the T cells in this system, we verified, using Thy-1 congenic strains, that the suppressor T cells induced were effectively derived from the transferred T cells and not from the host. The following strains of mice were selected for these studies: C57BL/6 (Ighb), B6.Ighn, and C57BL nu/nu. The NP-specific suppressor T cells generated in C57BL nu/nu mice reconstituted with T cells derived from Igh congenic B6.Ighn donors were investigated. Suppressor T cells were induced by i.v. administration of 10(4) NP-coupled B6.Ighn adherent cells. Six days later, the spleen cells from the reconstituted nude mice were treated with anti-NPb antibodies and complement before being transferred to C57BL/6 recipients immediately prior to antigen priming. Treatment with anti-idiotypic reagents depleted suppressor cell activity, which indicates that the suppressor cells obtained from C57BL/6 mice or C57BL nu/nu mice that have been reconstituted with B6.Ighn T cells bear NPb idiotype-related determinants. The data further demonstrate that the idiotype-related determinants expressed on NP-specific Ts1 are controlled not by the Ighn genotype of the T cell donor, but by the genotype of the C57BL nu/nu (Ighb) recipient host. In agreement with these findings, we further verified that the NP-specific suppressor T cells generated in C57BL nu/nu mice reconstituted with B6.Ighn mature T cells display the operational Igh restrictions of C57BL/6 mice and not of B6.Ighn mice. These experiments demonstrate how idiotypic elements expressed on the immunoglobulins of the host influence the specificity of the antigen receptor on T cells. Normally, Ts1 from B6.Ighn mice lack the NPb idiotype-related determinants and their suppressive activity is operationally restricted by the Ighn allotype. However, mature B6.Ighn T cells selected to respond to NP in C57BL nu/nu recipients display idiotype-related determinants and restriction specificities characteristic of the C57BL (Ighb) host. Thus, the environment in which Ts1 are induced and selected affects the Ts1 repertoire. How can we account for this phenomenon?

In order to investigate spatial variations in ventricular fibrillation (VF), activation rates during VF in pigs were estimated on a grid of 504 epicardial sites using the maximum entropy (ME) method. ME spectral estimates were obtained from unipolar electrograms recorded with a 21/spl times/24 array of epicardial electrodes (1 mm spacing) during electrically induced VF. The frequency associated with the most power in each ME spectrum was denoted the peak frequency (PFreq). The authors compared ME estimates of mean activation interval (1/PFreq) to mean activation intervals (MAI) obtained by picking the local minimum dV/dt. The Class III drug artilide was used to extend the range of activation rate. A significant positive correlation was found between 1/PFreq and MAI. ME estimates of 1/PFreq did not correlate better with MAI than previous estimates obtained using the Fast Fourier Transform. The spatial distribution of activation rate varied dynamically during the first 12 seconds of VF.