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Objective: To present an atypical case of massive ascites and hydrothorax after leuprolide acetate administration in a down-regulated woman undergoing assisted reproduction., Design: Case report., Setting: Centre for Reproductive Medicine, Department of Obstetrics, Gynaecology, and Neonatology, University of Parma, Parma, Italy., Patient(s): A 41-year-old, nulliparous, white woman who developed massive ascites and hydrothorax after administration of 0.50 mg/day of subcutaneous leuprolide acetate, beginning at the midluteal phase., Intervention(s): Down-regulation with the gonadotropin-releasing hormone analogue was discontinued, and therapy was started with furosemide 50 mg/day for 10 days., Main Outcome Measure(s): Successful medical reduction of ascites and hydrothorax., Result(s): Resolution of symptoms., Conclusion(s): A comprehensive MEDLINE search revealed this to be the first reported case of massive ascites and hydrothorax after leuprolide acetate administration (0.5 mg daily) in a down-regulated woman undergoing assisted reproduction. This case can be explained by an increase in capillary permeability, which resulted in a rapid fluid shift from the intravascular space into the third space. We believe that ascites in our patient resulted from an increase in estradiol in the ovaries, due to a direct action of the gonadotropin-releasing hormone analogue on the corresponding ovarian receptors in the first few days after the start of therapy.

We studied structural reorganization of the liver after toxic injury caused by a single injection of doxorubicin in a sublethal dose (10 mg/kg). The morphogenesis of doxorubicin injury to the liver is determined by two main pathogenetic factors: cytotoxic effect of doxorubicin and its metabolites on liver cell populations (primarily hepatocytes) and pronounced hemodynamic disorders in the greater circulation resulting from the development of chronic cardiac insufficiency. Changes in hepatocyte caused by doxorubicin manifest by fatty degeneration in the periportal zones and by pronounced lytic changes in the pericentral zones, most pronounced by day 30 of the experiment. Doxorubicin in the studied dose exhibited no cytostatic effect on the hepatocyte population. Hepatocyte proliferation, observed during the entire experiment, leads to an appreciable increase in their count and liver weight.

We report the first case of an adult presenting with respiratory symptoms caused by hepatic hydrothorax secondary to vitamin A intoxication. The patient was a 52-year-old woman who presented to the hospital with progressive dyspnea. Evaluation demonstrated mild elevation of her liver function tests, ascites, and a right pleural effusion. The patient consumed a variety of vitamins, including vitamin A. Her estimated vitamin A intake was at least 162,300,000 international units (IU) during 18 years. She dramatically escalated her dose the year before admission for a total acute dose of 98,550,000 IU, with a daily intake of 270,000 IU. The recommended daily allowance is 4,000 IU. A transjugular liver biopsy revealed histopathologic changes consistent with vitamin A toxicity: hypertrophy and hyperplasia of hepatic stellate cells, focal pericellular fibrosis, mild perivenular fibrosis, and minimal, predominantly microvesicular steatosis. Despite the absence of cirrhosis, pressure readings demonstrated portal hypertension. During her hospitalization, the patient's symptoms and biochemical profile improved. As the large and generally unregulated United States dietary supplement industry continues to grow, it is increasingly likely that individuals will present with the signs and symptoms of vitamin excess rather than vitamin deficiency. Physicians need to remain alert to the varied presentations and toxic manifestations of excessive vitamin use.

Clinical trials of immunotoxins in cancer patients have been limited in many cases by vascular leak syndrome (VLS). Recently, rats were identified as a model for VLS induced by BR96 sFv-PE40, a carcinoma-reactive single-chain immunotoxin. In this study, the toxin component of this immunotoxin, PE40, was found to be responsible for inducing hydrothorax in rats, thereby demonstrating that direct binding to the BR96 antigen was not essential to the onset of VLS. Mutational analysis of PE40 determined that both ADP ribosylation and proteolytic processing functions innate to Pseudomonas exotoxin A (PE) were necessary for PE40 to induce hydrothorax in rats; however, neither function by itself was sufficient for VLS induction. Additionally, nonsteroidal anti-inflammatory agents were found to block VLS in rats receiving BR96 sFv-PE40. These results demonstrate that the toxin component of PE-based immunotoxins induce VLS and suggest agents for clinical management of the toxicity.

Immunotoxins are hybrid molecules composed of a cell-surface binding domain and a protein toxin moiety that together target specific cell populations for elimination. These agents represent a promising approach for the treatment of many human diseases, most notably cancer. However, it has recently become clear that many immunotoxins when used in human clinical trials induce vascular leak syndrome (VLS), restricting the administration of doses necessary to achieve good therapeutic responses. The lack of an appropriate animal model has hindered efforts to understand and prevent immunotoxin-induced VLS. We have found that in rats, intravenous administration of the single-chain immunotoxin BR96 sFv-PE40 results in symptoms that closely resemble VLS seen in human immunotoxin trials. A large fluid accumulation in the thoracic cavity was observed, along with an increase in hematocrit and body weight and a decrease in serum albumin. The VLS was apparent within 24 hr after administration of immunotoxin and was seen in both immunocompetent and athymic rats. Similar symptoms were not found in mice even at lethal doses. Prophylactic administration of the corticosteroid dexamethasone resulted in prevention of VLS and survival of rats injected with what would otherwise be lethal doses of BR96 sFv-PE40. Prophylactic treatment with dexamethasone in rats xenografted with human tumors either did not inhibit or minimally inhibited the antitumor activity of BR96 sFv-PE40. The use of prophylactic corticosteroids should be considered for immunotoxin clinical trials, since it may improve therapeutic efficacy by decreasing the dose-limiting toxicity of VLS.

Interleukin (IL)-2 is known to induce vascular leak syndrome (VLS), which was suggested to be mediated by immune system-derived cytokines, including tumor necrosis factor (TNF). To characterize the role of TNF in IL-2 toxicity in C3H/HeN mice, we used two approaches to downregulate TNF production in vivo: treatment with dexamethasone (DEX) and induction of endotoxin (lipopolysaccharide) (LPS) tolerance by a 4-day pretreatment with LPS (35 micrograms/mouse/day). Mice were then treated with IL-2 for 5 days (1.8 x 10(5) IU/mouse, twice daily). Both DEX and LPS tolerance blocked development of hydrothorax in IL-2-treated mice and inhibited TNF induction. DEX and LPS tolerance also ameliorated IL-2 toxicity in terms of decrease in food intake and inhibited the increase of the acute-phase protein, serum amyloid A (SAA). The IL-2 activation of splenic natural killer (NK) cell activity was also diminished by DEX and, to a lesser extent, by LPS-tolerance. Treatment with IL-2 also caused induction of the superoxide-generating enzyme xanthine oxidase (XO) in tissues and serum and induced bacterial translocation in the mesenteric lymph nodes (MLN). These data suggest that multiple mechanisms, including NK cell activity, cytokines, and reactive oxygen intermediates, might be important in the vascular toxicity of IL-2.

Pulmonary edema and hydrothorax were observed in mature swine that died approximately 5 days after consuming corn screenings. These postmortem observations were reproduced in younger pigs that died within 1 week when fed the corn screenings under experimental conditions. Additionally, pulmonary edema and hydrothorax were induced in a pig that died after receiving 4 daily intravenous injections of fumonisin B1, a toxic metabolite produced by Fusarium moniliforme.

Pulmonary edema and hydrothorax were observed in mature swine that died approximately 5 days after consuming corn screenings. These postmortem observations were reproduced in younger swine (16-24 kg) that died within 1 week when fed the corn screenings under experimental conditions. Additionally, pulmonary edema and hydrothorax occurred in a pig (7.1 kg) that died after receiving 4 daily intravenous injections of fumonisin B1. A fungus was isolated from the corn screenings that is identical to Fusarium moniliforme MRC-826 in colony morphology and under microscopic examination.

Cardiac toxicity of the new anthracycline antitumour antibiotics violamycin BI (V) and carminomycin (C) was studied in comparison with daunorubicin (D). Rabbits were intravenously given total doses of 0.1-1.5 mg/kg V or C, and 0.64-18 mg/kg D, respectively, twice weekly for one month. When examined two to six days, two and four weeks, respectively, after the last drug administration the gross findings consisted of hydropericard, hydrothorax and ascites in some animals. Histologically, loss of striation and focal necrosis of cardiac muscle cells and subsequently chronic inflammatory reactions and/or proliferation of mesenchyma cells were mostly found. These alterations were somewhat more pronounced in rabbits treated with V than in animals received D or C. At equitoxic doses of the antibiotics tested the ultrastructural lesion in the myocardial cells were altogether less marked after treatment with D than with C or V.

In supine rabbits injection of 2 ml of saline into the lower right diaphragmatic region increased pleural liquid pressure at the injection point and, to a minor extent, on the costal and mediastinal side, indicating a redistribution of liquid among the pleural compartments. Over a period of 120 min end-expiratory liquid pressure on the diaphragmatic and costal surfaces approached the control value as a result of local reabsorption. No difference in the time course of liquid pressure was found on injection of either saline or homologous plasma. This was confirmed by measuring the volume of saline or plasma remaining in the cavity 90 min after injection; the net absorption flow amounted to 0.22 ml . kg-1 . h-1. These results suggest that local absorption mechanisms are relatively independent of the Starling pressure gradients acting across the pulmonary-perfused (-10.2 and 6.6 cmH2O with saline and plasma, respectively, the negative sign indicating a reabsorption gradient) and systemically perfused mesothelium (3.3 and 20.1 cmH2O with saline and plasma, respectively).

Chronic Adriamycin (ADR) toxicity was produced in 50 weanling rabbits by weekly injections of 2.4 mg of ADR/kg of body weight for up to 17 weeks. An evaluation was made of the protective value of weekly injected supplements, given 24 hours before each ADR injection, which included: (a) low-dose vitamin E (alpha-tocopherol acetate, 17 mg/kg) (b) high-dose vitamin E (alpha-tocopherol acetate, 170 mg/kg); (c) selenium (as sodium selenite, 0.06 mg/kg); and (d) combined low-dose vitamin E and selenium. The incidence of cardiomyopathy was high in both supplemented and unsupplemented rabbits. Mean cardiomyopathy scores were low in the unsupplemented rabbits and moderatey high in the supplemented rabbits (that survived longer), but were lower in rabbits given high-dose vitamin E than in the other supplemented groups. Supplements of vitamin E, selenium, or both prolonged survival of animals treated continuously with ADR, but only supplements of large amounts of vitamin E provided any evidence of even partial protection against chronic cardiotoxicity.

Primary thiomides such as thiobenzamide (TB) are well known hepatotoxins in the rat. Among para-substituted TB derivatives relative hepatotoxicity varies in accordance with the electronic properties of the parasubstituent. In contrast, several N-substituted TBs have been found to be potent lung toxins in rats and mice. For N-methylthiobenzamide (NMTB) the LD50 was found to be 0.315 (95% confidence interval (CI) 0.228-0.436) mmol/kg in the rat and 0.224 (95% CI 0.191--0.264) mmol/kg in the mouse. The N-mono-substituted TBs produce alveolar and perivascular pulmonary edema, together with massive pleural effusions (hydrothorax). In this regard their toxicity resembles qualitatively that of the arylthioureas. Furthermore, pretreatment of rats with sub-lethal doses of NMTB was found to protect them against subsequent challenge with supra-lethal doses. N,N-Dimethylthiobenzamide (DMTB) also causes lung injury in the rat, but only at much higher doses than with the N-mono-substituted TBs. The similarity in toxic responses elicited by the N-mono-substituted TBs and the arylthioureas is paralleled by similarities in their chemical structures and their metabolic disposition which involves (among other things) S-oxygenation by the microsomal flavin-containing monooxygenase (EC 1.14.13.8). Thus, a possible role for S-oxidized metabolites in the lung toxicity of these compounds must be considered.

A case of hyperstimulation syndrome secondary to Pergonal therapy is presented. Successful management was based principally on severe sodium and fluid restriction without the use of volume expanders. The rationale for this therapeutic approach is presented and discussed. Although this iatrogenic disease should be virtually eliminated with the monitoring of daily urinary estrogens, severe hyperstimulation may still occur as a result of laboratory error.