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We have recently demonstrated that ritanserin, a serotonin 5-hydroxytryptamine receptor antagonist void of systemic effects, caused a significant reduction of portal pressure in conscious cirrhotic dogs. The mechanism by which ritanserin lowers portal pressure is poorly defined. We investigated the splanchnic and systemic hemodynamic effects of ritanserin (0.63 mg/kg body wt i.v., a dose known to completely inhibit binding of 5-hydroxytryptamine to its receptors), in conscious and unrestrained cirrhotic rats (n = 13). Heparinized catheters were placed into the portal vein, inferior vena cava, aorta, and left ventricle with exit from the neck. Hemodynamic studies were performed 4 h after consciousness was regained. Cardiac output and regional blood flows were measured using radiolabeled microspheres and the reference sample method. Sixty minutes after administration, ritanserin caused a significant reduction of portal pressure (-17%) with minimal changes in portal venous inflow (+3%). Portal vascular resistance decreased significantly (-23%), whereas splanchnic arteriolar resistance was similar before and after ritanserin. A significant increase in mean arterial pressure (+5%) and cardiac output (+22%) was observed. Our results suggest that ritanserin lowers portal pressure through a mechanism separate from portal venous inflow. This effect could be due to changes in intrahepatic or on portocollateral resistances, or both. These findings support the potential use of this new agent in the treatment of portal hypertension.

This study was carried out to determine the effect of perioperative blood transfusions on the survival of patients operated on for colorectal cancers. Cox's regression analysis was applied to 281 patients operated for cure of Dukes' stage A, B or C disease. Other variables studied were age, sex, tumour location, and preoperative hemoglobin, lymphocyte and albumin values. Perioperative deaths, pre- and postoperative immunodepression, neoplasia in situ, nonresections and stage D disease were excluded. It was found that the number of units of blood transfused had a strong influence on the prognosis of patients with colorectal cancer, particularly colonic cancers, but the effect could not be demonstrated when rectal cancers were studied separately, perhaps because of the small number of cases. The mechanism of action of blood transfusions seems to be independent of the other analysed variables. The authors suggest that perioperative blood transfusions may have an immunomodulatory effect in patients with colonic cancer, as already shown in recipients of transfused kidney allografts.

An experimental model of canine normothermic renal ischemia was used to determine whether lysosomal urinary enzyme excretion reflects the extent of ischemic cellular injury, as assessed by subsequent renal function (serum creatinine level) and morphologic changes. The value of a lysosomal membrane-stabilizing agent (methylprednisolone) in protecting kidneys from ischemic damage by preventing lysosomal enzyme release was assessed. Results showed conclusively that urinary enzyme activities of beta-galactosidase and N-acetyl-beta-glucosaminidase are valuable indicators of renal cellular damage and functional outcome after ischemic injury, and that methylprednisolone at a dose of 30 mg/kg, given intravenously 1 hour before a 1-hour period of normothermic ischemia, protects the kidney both biologically and morphologically, by reducing the excretion of lysosomal enzymes after revascularization.

The glomerular fibrinolytic activity (GFA) was measured during the development of glomerulonephritis induced by the intravenous injection of horse or rabbit antiglomerular basement membrane antibodies in rats either untreated or preimmunized with horse or rabbit Ig. A variety of nephritides was produced ranging from proteinuria with no or mild changes in glomerular architecture to severe diffuse proliferative glomerulonephritis with close to 100% crescent formation. GFA was measured on preparations of isolated glomeruli using a radioassay based on lysis of 125I fibrin adsorbed on a solid phase. In some experiments a fibrin plaque technique was also used. Both methods clearly demonstrated a marked increase in GFA with a good correlation between the two sets of results when the glomerular architecture is preserved. The increase in GFA is related both to the severity of the nephritis estimated by the percentage of glomeruli showing crescent formation and to the extent of the fibrin deposits. The results therefore indicate that the persistence of fibrin in the glomeruli and particularly in crescents is not due to a loss of GFA.

Following gastrectomy for locally advanced adenocarcinomas, three patients developed microangiopathic hemolytic anemia and renal failure shortly after completing courses of adjuvant chemotherapy with mitomycin and 5-FU. These complications progressed despite cessation of chemotherapy, and all three patients died of noncardiogenic pulmonary edema precipitated in two cases by blood transfusions. At autopsy, two patients had no residual carcinoma and all had a diffuse microangiopathy involving mainly the kidneys and lungs. There was intimal hyperplasia of many arterioles sometimes associated with complete occlusion of the lumen, prominent nuclear atypia in many capillary cells, and numerous capillary fibrin thrombi. Direct immunofluorescence studies revealed extensive fibrinogen-fibrin deposits in the vascular lesions. Chemotherapy-induced microangiopathic hemolytic anemia and renal failure may predispose patients to fatal episodes of noncardiogenic pulmonary edema that can be triggered by blood transfusions.

Adriamycin (ADR) can be linked to DNA without loss of its antitumoral activity while reducing the acute toxicity of free ADR (Deprez--DeCampeneere et al., 1979, 1980). However, the potential chronic toxic effects of both forms of ADR are poorly documented. For such a study, it is necessary to establish the sequence of treatment allowing the administration of a sufficient amount of drugs to induce chronic toxicity and a schedule leading to prolonged survival of animals. In this study, 24 Lewis rats were injected twice a week during four weeks with either free or DNA-linked ADR, and three dose levels were tested: 4, 2 and 1 mg/kg. Our results indicated that the total cumulative dose of ADR should not exceed 8 mg/kg over one month, if prolonged survival is desired. The binding of ADR to DNA seemed also to reduce the acute toxic effects induced by free ADR, in rats. However, such a beneficial effect was not observed when the chronic nephrotoxicity was considered since characteristic renal lesions were observed in all long-term survivors, whatever the dose and the form of ADR received.

We have generated three hybridoma-producing monoclonal antibodies (MAs) that show a different spectrum of reactivity to human mammary tissues. Two of these antibodies, 1F10B4 and 1F10G2, recognize a cytoplasmic determinant highly expressed in most of the primary and metastatic breast carcinomas studied, and weakly (or not at all) in normal breast and nonbreast tissues. 3C6F9 detected a surface determinant common to both normal and neoplastic mammary epithelium. Five hundred hybridomas were obtained from the fusion of NS-1 myeloma cells with spleen cells of mice hyperimmunized with the well-characterized human breast carcinoma cell line BT-20. After the initial screenings and clonings, three monoclonal antibodies (1F10B4, 1F10G2, and 3C6F9) showing a restricted range of reactivity were selected for further investigation. These three antibodies recognized a panel of neoplastic mammary cell lines; however, the degree of reactivity could not be correlated to any of the various characteristics of these epithelial cell lines. Moreover, immunofluorescence analysis of acetone-fixed cryostat section showed that 1F10B4 and 1F10G2 recognize the vast majority of the 37 primary and metastatic breast cancers tested, binding strongly to 47% and 67% of them respectively. Only one of the primary carcinomas was not recognized by 1F10B4. On the other hand, these two MAs reacted weakly or not at all with normal breast and nonbreast tissues showing only few focal reactivities with the luminal pole of some ducts of the breast; very weak staining in renal tubular epithelial cells, in few keratinocytes and epithelial cells lining some sebaceous glands in the skin; and a moderate staining in biliary ducts of the liver. All mesenchymal structures including smooth and striated muscle tissues, lymph nodes, and connective tissue were negative. On the other hand, 3C6F9 recognized a more limited number of human mammary tumors and reacted with normal ductal epithelium in the breast and with nonbreast tissues. Because of their wide spectrum of reactivity with breast cancer cells and restricted recognition of normal mammary tissues, their cytoplasmic localization, and their heterogeneous distribution within a single neoplasm, 1F10B4 and 1F10G2 are now being used to characterize antigenic phenotypes of tumor-associated antigens in retrospective studies performed on conventional formalin-fixed, paraffin-embedded human mammary carcinomas.

Necroptic examination of a male newborn baby revealed multiple anomalies of the heart, including multiple cardiac rhabdomyomas, aortic valvular atresia, left cardiac hypoplasia, hypoplasia of proximal aorta and hypertrophy of the right heart. Tuberous sclerosis was not present. In are instances, the association of cardiac rhabdomyomas and other congenital cardiac malformations have been reported but the association documented here has not been, to our knowledge, previously described.

The classical triad of hemolytic uremic syndrome (microangiopathic hemolytic anemia, severe thrombopenia, and renal failure) developed de novo in three of our renal transplanted patients under cyclosporin A treatment. The predominant morphologic findings in the grafts consisted of glomerular and arteriolar thrombosis as well as arteriolonecrosis, all features of the syndrome. In one instance, ischemic bowel disease supervened after graft removal and was associated with persistent low grade microangiopathic process. De novo hemolytic uremic syndrome has been reported in patients treated with cyclosporin A following bone marrow or liver transplantation as well as in a few renal graft recipients. This peculiar form of cyclosporin A nephrotoxicity should not be confused with acute rejection of the renal transplant.

Between November 1979 and April 1984, 790 consecutive pregnant women who considered themselves as having a "normal" pregnancy were followed in private practice from 9 weeks' gestation until 6 weeks post partum. The women had no pre-existing disease or problem classified as a risk to the pregnancy at the time of their first visit, had a singleton pregnancy and gave birth at Notre-Dame Hospital, Montreal. Maternal complications occurred during the course of pregnancy in 181 women (23%). Complications were mostly related to obstetric conditions (10%), such as preterm labour, intrauterine growth retardation (IUGR) and antepartum hemorrhage, or to medical conditions (12%), the most prevalent of which was hypertension (77% of medical conditions). Neonatal complications occurred in 183 infants (23%). The corrected perinatal death rate was 2.5 per 1000. Prematurity, IUGR and dysmaturity/postmaturity accounted for nearly half of the complications. Hyperbilirubinemia occurred in 7% of the cases. Among women without any maternal complications during pregnancy, the frequency rate of neonatal complications was 19%, compared with 23% among the entire group of 790 women. Our results suggest that the absence of maternal complications does not protect the infant from a neonatal complication. Further refinement is needed to identify markers of obstetric, medical and neonatal complications in pregnancies with no risk factors.

A preparation of cyclosporine (CsA) in liposomes was tested in the rat to evaluate its effectiveness in reducing CsA nephrotoxicity. The drug was injected intravenously in unilaterally nephrectomized Lewis rats at a daily dose of 25 mg/kg for 14 days, either in a cremophore solution (eight rats) or in a preparation of liposomes (eight rats). Another group of four animals received the cremophore solution alone. Overall, rats treated with the CsA-liposome preparation had reduced toxicity, exhibiting better survival rates and less weight loss than those treated with the CsA-cremophore. Incorporating CsA into liposomes induced a statistically significant (p less than 0.05) reduction in the otherwise progressive increase of serum creatinine during week 2 of the experiment. Following administration of CsA-liposome preparation, epithelial cells of the proximal renal tubules appeared morphologically normal, without evidence of vacuolization, which is characteristic of CsA nephrotoxicity and was seen in the CsA-cremophore group. Although the exact mechanism is not clearly understood, it is likely that the tissue distribution of CsA, when incorporated into liposomes, is modified in favour of the reticuloendothelial cells, thereby sparing highly sensitive, but non-target organs such as the kidneys.

The potential nephrotoxicity of Mitomycin-C (MMC) was studied in 17 autopsies from patients treated with this drug, usually in association with other anti-neoplastic agents. Renal functional deterioration was present in seven cases while urinalysis showed an overt proteinuria and hematuria in six and four instances, respectively. Four of these patients also developed a severe microangiopathic hemolytic anemia (MAHA) and thrombopenia. Histological examination did not reveal residual tumor in three of them. However renal lesions similar to those observed in the hemolytic-uremic syndrome (HUS) were associated with glomerular mesangiolytic changes and nuclear atypias in glomerular and tubular cells. Immunofluorescence and ultrastructural studies confirmed these findings. In other patients, variable degrees of cellular atypias and of mesangiolysis were observed. The severity of the glomerular, vascular, and tubular lesions correlated with the total dosage of MMC received. The nephrotoxic potential of MMC seems to be delayed in onset and dose related.

The chemotherapeutic effectiveness of the lysosomotropic Adriamycin-DNA complex has been demonstrated experimentally. This study evaluated the immunosuppressive activity of the complex on renal allografts in rats of the Buffalo-Lewis strain. Six rats receiving no treatment served as a control. Five rats received DNA along (at a dose equivalent to that in the complex), seven received the Adriamycin-DNA complex (molar ratio of DNA mononucleotide to Adriamycin, 20:1) and five were given free Adriamycin. Adriamycin, free or linked to DNA, was injected as follows: 2 mg/kg on days 2, 6 and 9 and 1 mg/kg on day 13 after transplantation. The Adriamycin-DNA complex prevented renal allograft rejection in the early postoperative period, by delaying for more than a week, the increase in serum creatinine levels in animals receiving transplants. Histologic examination of renal grafts in these rats confirmed the reduced severity of acute cellular rejection. There was also functional and morphologic evidence of reduced toxicity of Adriamycin when linked to DNA. The beneficial effect of such a drug should be attributed to its lysosomotropic mechanism of activity.

A prospective study of blood pressure recording was conducted in 1000 patients, at each antenatal visit, with the use of an automatic random-zero sphygmomanometer. In 46 patients, among 808 primigravid women, who developed preeclampsia, the diastolic and mean blood pressures were significantly elevated compared to values at the first antenatal visit (p less than 0.01, 9 to 12 weeks). This difference was sustained throughout pregnancy until delivery by at least 10 mm Hg as compared to pressures in the normotensive group. Sensitivity for predicting preeclampsia early in pregnancy with an elevated blood pressure measurement (130 to 135/80 to 85 mm Hg) ranged from 16% to 57% while specificity ranged from 75% to 98%. The results substantiate an early vasospasm (9 to 12 weeks) in those women destined to develop preeclampsia.

Of 939 patients treated by radiotherapy for carcinoma of the cervix at the hôpital Notre-Dame in Montreal, between 1979 and 1981, 275 (29.3%) had digestive, urologic, gynecologic, vascular, osseous and cutaneous complications. Surgery was necessary to treat 73 complications in 55 patients (5.9%): 42 digestive (25 occlusions, 13 fistulas and 4 perforations); 22 urologic (16 occlusions, 5 fistulas, 1 hemorrhage); 6 gynecologic (3 hemorrhage and 3 uterine necrosis); 1 cutaneous, 1 vascular and 1 osseous necrosis. No direct correlation was found between the incidence of the complications and certain predisposing factors such as the type of radiotherapy, patients' age, stage of the disease and gynecologic surgery before radiotherapy. However, there was a strong correlation between the incidence of complications and the dose of radiotherapy and the need for gynecologic surgery after radiotherapy. High morbidity was observed in the 55 patients treated surgically: they had to undergo a mean of 2.36 operations each, 2.98 general anesthetics, 1.81 hospitalizations (mean duration 75.7 days); 21 had one or more definitive stomas. The death rate was 5.45%. Surgical treatment was individualized. Limited resections were performed for occlusions, fistulas and perforations whenever it was technically feasible to treat digestive and urologic complications. A bypass procedure was used when resection would have been too extensive or dangerous. The majority of rectal lesions were treated by colostomy and a Hartmann procedure.

The early nephrotoxicity of free and DNA-bound adriamycin (ADR) was compared in left nephrectomized rats. Free ADR induced progressive renal failure within 3 weeks, in association with renal changes characterized by severe tubular distention and vacuolization of podocytes in glomeruli. On the contrary, renal function remained normal and renal lesions were discrete in animals treated with ADR bound to DNA. Thus, the binding of ADR to DNA seems to reduce the early nephrotoxicity of free ADR.