Pituitary gland gumma in congenital syphilis after failed maternal treatment: a case report.

A preterm, very low birth weight infant was born to a mother with early latent syphilis who was treated 10 days and 3 days before delivery with 2.4 mU of benzathine penicillin. The infant had clinical, laboratory, and radiographic abnormalities consistent with congenital syphilis, ie, a Venereal Disease Research Laboratory test titer that was fourfold greater than was the maternal titer, hepatosplenomegaly, abnormal liver function tests, pneumonitis, osteochondritis of the long bones, and cerebrospinal fluid (CSF) examination showing a reactive Venereal Disease Research Laboratory test, pleocytosis, and elevated protein content. The infant died on the third day of life, and an autopsy revealed an evolving gumma of the anterior pituitary. Immunoglobulin M immunoblotting of serum and CSF was positive, and polymerase chain reaction detected Treponema pallidum DNA in endotracheal aspirate and CSF. This case highlights the pathologic abnormalities observed in congenital syphilis and focuses on the rare finding of an evolving anterior pituitary gumma. Furthermore, it documents the failure of maternal syphilis treatment during the last 4 weeks of pregnancy to cure fetal infection and supports the recommendation that all infants born to mothers with syphilis treated during the last 4 weeks of pregnancy should receive penicillin therapy.

Diquat- and acetaminophen-induced alterations of biliary efflux of iron in rats.

The effects of diquat on the biliary efflux of nonheme iron in rats were studied as a means of examining the possible effects of diquat metabolism on hepatocellular iron metabolism and the association of altered iron metabolism with the initiation of acute hepatic necrosis. Administration of hepatotoxic doses (0.1 mmol/kg) of diquat to male Fischer-344 rats increased biliary iron concentrations from 6 microM to more than 15 microM. However, increases in biliary efflux of iron were not observed during the first 60 min following exposure to diquat, despite the rapid increases in biliary glutathione disulfide concentrations, which increased maximally within 40 min. Biliary efflux of iron was not altered by diquat in Sprague-Dawley rats, which are resistant to hepatic necrosis in response to diquat, despite the marked oxidant stress responses observed in these animals. Conversely, hepatotoxic doses of acetaminophen (1500 mg/kg) caused significant decreases in biliary iron efflux. The rapid decreases in biliary iron caused by acetaminophen and the delay in diquat-induced iron efflux suggested the possibility that some fraction of the biliary iron was being excreted as reversibly formed GS-Fe2+ chelates, with inhibition of export by glutathione disulfide (GSSG) in the case of diquat, or by 3-(glutathion-S-yl)-acetaminophen (GS-AAP) in the case of the acetaminophen-treated animals. However, 50-200 mg/kg doses of acetaminophen showed little effect on biliary iron excretion despite producing biliary GS-AAP conjugate concentrations almost 1000 times the 6 microM concentrations of iron, which would not appear to support the hypothesis of excretion of GS-Fe2+ chelates. The data demonstrate a significant effect of diquat on hepatic iron metabolism in Fischer-344 rats, and the possible importance of this iron redistribution to reactive oxygen-mediated cell damage in vivo is indicated by the absence of similar responses in diquat-treated Sprague-Dawley rats.

Attenuation of acetaminophen hepatotoxicity in mice as evidence for the bioavailability of the cysteine in D-glucose-L-cysteine in vivo.

A substantial fraction of the cysteine added to total parenteral nutrition (TPN) solutions is converted to the corresponding thiazolidine derivative, while in solution with relatively large concentrations of glucose typical of TPN (700 mM and higher). It was recently reported (Roberts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidine, D-glucose-L-cysteine (DGC), offered no significant protection against the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, suggesting that the cysteine present as DGC is poorly bioavailable in vivo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/kg of acetaminophen sustained hepatic injury, estimated by elevations in plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i.p. prevented the rise in plasma ALT activities, apparently through support of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetaminophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetaminophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly greater protection than did DGC at the higher dose of acetaminophen. Given 4 h before acetaminophen, DGC attenuated acetaminophen-induced increases in plasma ALT activities significantly, whereas NAC was without effect. These results indicate that the cysteine in DGC is at least partially bioavailable in vivo and, further, that DGC may function as a slow release formulation of cysteine.

Hyperoxic lung injury in Fischer-344 and Sprague-Dawley rats in vivo.

Supplemental oxygen remains an important therapy for pulmonary insufficiency, despite the potential adverse effects of hyperoxic exposures. Recently, He et al. reported that hyperoxic ventilation more readily damaged isolated perfused lungs from Fischer-344 rats than from Sprague-Dawley rats (Am. J. Physiol. 259:L451), which correlates with the previously reported strain differences in hepatic responses to diquat-induced oxidant stress in vivo (J. Pharmacol. Exp. Ther. 235:172). We therefore examined the differences in hyperoxic lung injury in Fischer-344 and Sprague-Dawley rats in vivo. Adult male rats were exposed to > 95% O2 and were sacrificed after 24, 48, or 60 h. Control animals were maintained in room air. Dramatically greater increases in pleural effusions and bronchoalveolar lavage protein concentrations in response to hyperoxia were observed in the Fischer-344 rats than in the Sprague-Dawley rats (p < .05 at both 48 and 60 h for both measurements). Additionally, the glutathione concentrations in alveolar lining fluid decreased from 800 microM to 115 microM in Fischer-344 rats after 60 h of > 95% O2, but did not change in Sprague-Dawley rats. We conclude that the greater susceptibility of Fischer-344 than of Sprague-Dawley rats to hyperoxic lung injury in vitro reported previously also is observed in vivo and that this strain difference offers unique opportunities to study mechanisms of hyperoxic lung injury.

Investigation of possible mechanisms of hepatic swelling and necrosis caused by acetaminophen in mice.

Vascular congestion and liver swelling have long been recognized as features of the hepatotoxic effects of acetaminophen (AAP) in mice and rats and have been proposed as contributing factors to the eventual extent of necrosis produced. Neutrophil accumulation in the hepatic microcirculation has been proposed as being responsible for the blockage of hepatic blood flow and thereby the expansion of the region of damage. We therefore determined in mice the effects of hepatotoxic doses of AAP on the messenger RNA for intercellular adhesion molecule-1 (ICAM-1), which is a critical determinant of neutrophil adhesion, activation and ultimately of neutrophil-mediated tissue injury. Hepatotoxic doses of AAP did not upregulate ICAM-1 messenger RNA. However, doses of bacterial lipopolysaccharide (LPS) did cause a rapid and dramatic increase in ICAM-1 message, which was accompanied by a much greater hepatic accumulation of neutrophils, but which led to only scattered single cell necrosis. In addition, we investigated the effects of pentoxifylline (PTX) on AAP-induced vascular congestion and on hepatic necrosis as evaluated histologically and by measurement of plasma transaminase activities. Although PTX has been shown to increase blood cell deformability and improve vascular perfusion in a number of animal models of restricted blood flow, and is used in humans for the treatment of intermittent claudication, we found no decrease in AAP-induced hepatic swelling or in AAP-induced necrosis in response to PTX. With some dosing regimens, PTX-treated animals proved to be slightly more susceptible to AAP, which may be related to the reported potentiation of the cytotoxicities of a number of alkylating anti-cancer drugs by PTX and other methylxanthines. We conclude from these studies that upregulation of ICAM-1 and subsequent adhesion and vascular plugging by neutrophils are not significant determinants of AAP-induced liver swelling and necrosis and that whatever hemorheological advantages PTX might offer in AAP-induced hepatic damage appear to be overshadowed by effects that potentiate the toxic responses.

Pathophysiological consequences of enhanced intracellular superoxide formation in isolated perfused rat liver.

The potential toxicity of enhanced intracellular reactive oxygen formation was investigated in isolated perfused livers of male Fischer rats. The presence of the redox-cycling agent diquat in the perfusate (200 microM) increased the basal efflux of glutathione disulfide (GSSG) into bile (2.65 +/- 0.26 nmol GSH-equivalents/min per g liver wt.) and perfusate (0.55 +/- 0.15 nmol/min per g) approximately 10-fold. Since no evidence was found for degradation of GSSG in the biliary tract of these animals, it could be estimated that diquat induced a constant O2- generation of approximately 1000 nmol/min per g liver wt for 1 h. Thus, reactive oxygen formation under these conditions was 1-2 orders of magnitude higher than under various pathophysiological conditions. Only minor liver injury (release of lactate dehydrogenase activity) was observed. To increase the susceptibility of the liver to the oxidant stress, animals were pretreated in vivo with 200 mg/kg body wt. phorone, which caused a 90% depletion of the hepatic glutathione content, 100 mg/kg ferrous sulfate, a combination of phorone and ferrous sulfate, or 40 mg/kg BCNU, which caused a 60% inhibition of hepatic GSSG reductase. Only the combined treatment of phorone + ferrous sulfate or BCNU caused a significant increase of the diquat-induced liver injury. Our results demonstrated an extremely high resistance of the liver against intracellular reactive oxygen formation (even with impaired detoxification systems) and can serve as reference for the evaluation of potential contributions of reactive oxygen to liver injury in various disease states.

The effects of cadmium on ethanol self-administration using a sucrose-fading procedure.

Rats were exposed for 70 days to either a diet containing 100 ppm cadmium (Group Cadmium) or a control diet with no additives (Group Control). Subsequently, all animals were trained to lever press for a 20% sucrose solution. Across several phases, sucrose was faded out as the reinforcer and gradually replaced with a 10% ethanol solution. A subsequent operant choice (concurrent) test, during which pressing one lever resulted in a dipper presentation of ethanol and the other lever provided water, was followed by a single-lever test where sucrose was reinstated as the reinforcer. The results showed that although cadmium-treated rats lever pressed more than controls during the early phases of the sucrose-fading procedure, animals exposed to cadmium lever pressed at lower rats than controls for ethanol during the concurrent test. There were no group differences on the final sucrose test. The possibility that cadmium may alter sensitivity to ethanol is discussed.