Primary hyperaldosteronism caused by adrenocortical carcinoma

Since the syndrome of primary hyperaldosteronism was described by Jerome Conn in 1955, over 300 patients with this disorder have been identified in the medical centers of Vanderbilt University and the University of Michigan. The most frequent cause of this endocrinopathy has been a solitary adenoma of the adrenal cortex (72%); bilateral adrenocortical hyperplasia has been the cause of primary hyperaldosteronism in 27% of cases; less frequently, the cause has been multiple and/or bilateral adenomas (1%). During the last 4 years in these 2 medical centers, we have encountered 3 patients who have had biochemically proven primary hyperaldosteronism due to adrenocortical carcinoma. Each of these unusual cases is summarized with review of the recent literature.

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Resumen Desde la descripción del síndrome de hiperaldosteronismo primario por Jeremo Conn en 1955, más de 300 pacientes con esta entidad han sido identificados en nuestros 2 centros médicos, la Universidad de Vanderbilt (Nashville) y la Universidad de Michigan (Ann Arbor). La causa más frecuente de esta endocrinopatía ha sido el adenoma solitario de la corteza suprarrenal (72%); la hiperplasia adrenocortical bilateral ha sido la causa del hiperaldosteronismo primario en 27% de los casos; con menor frecuencia se han presentado los adenomas multiples y/o bilaterales (1%). En los 4 últimos años hemos encontrado 3 pacientes con hiperaldosteronismo primario comprobado bioquímicamente producido por carcinoma adrenocortical. Se presenta cada uno de estos casos poco usuales junto con una revisión de la literatura reciente.

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Résumé Depuis que le syndrome d'hyperaldostéronisme primitif a été décrit par Jerôme Conn en 1955 plus de 300 sujets qui en étaient victimes ont été identifiés à la Vanderbilt University de Nashville et à l'University of Michigan de Ann Arbor. La cause la plus fréquente de cette endocrinopathie répond à un adénome solitaire de la cortico-surrénale (72%) alors que l'hyperplasie corticale des 2 surrénales est plus rarement à son origine (27%), les adénomes multiples et/ou bilatéraux étant rarissimes (1%). Au cours des 4 dernières années 3 cas d'hyperaldosteronisme dû à un cancer de la cortico-surrénale ont été observés dans les 2 centres. Chacun de ces cas exceptionnels est exposé cependant que la littérature récente concernant l'hyperalderosteronisme est analysée.

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Presented at the International Association of Endocrine Surgeons in Paris, September 1985.     

Reversal of fulminant hepatic failure using an extracorporeal liver assist device.

Liver transplantation is currently the only effective therapy for patients with fulminant hepatic failure. The availability of an artificial liver could bridge these patients through the relatively brief crisis period and allow their own livers to regenerate, providing a more favorable outcome and sparing the trauma and expense of transplant. We have developed a device consisting of a highly differentiated human liver cell line cultured in a hollow fiber cartridge. This device is capable of supporting dogs with acetaminophen-induced fulminant hepatic failure for a period long enough for their own livers to resume function. Even though liver function tests such as albumin and prothrombin time became extremely abnormal during the course of the experiment, the dogs did not become encephalopathic. Two of the three treated animals recovered sufficient liver function after 42 to 48 hr of treatment that they could be disconnected from the device, and they survived the experiment. Histological results and serum ALT levels suggest that the device affected the course of the disease in two animals, allowing recovery of hepatocytes that would otherwise have lysed. In the third animal, regenerative nodules demonstrated that, even in the presence of severe liver injury, the device was capable of supporting total liver function.     

Presurgical electroencephalographic patterns and outcome from anterior temporal lobectomy.

We reviewed data from 48 patients after anterior temporal lobe resection for medically intractable epilepsy. All had ictal electro-encephalographic (EEG) evidence of unilateral temporal lobe onset. Depth electrodes were used in 19 patients. Successful surgical outcome correlated significantly with factors that suggested a temporal lobe focus, particularly in the interictal scalp EEG. The most successful outcome occurred in patients with well-localized unilateral interictal temporal spikes (100% improved). The group with well-localized bilateral temporal spikes also did well (76% improved). Patients with extratemporal spread of the interictal spike on scalp EEG, either unilaterally or bilaterally, did less well. Only one third improved, despite extensive extracranial and intracranial monitoring, when indicated. The interictal scalp EEG may be the only EEG necessary for the presurgical evaluation of selected patients with intractable temporal lobe epilepsy.     

Activity involvement, risk-taking, demographic variables, and other drug use: prediction of trying smokeless tobacco

Four activity participation variables (clubs, sports, church, and parties); two indices of "risk-taking" (preference for risk-taking, getting into trouble at school); three demographic variables (sex, ethnic group, socioeconomic status); and two drug use variables (trial of cigarettes and alcohol) were examined as correlates and prospective predictors of trial of smokeless tobacco in two cohorts of seventh graders in urban Los Angeles. The data were analyzed separately for males and females. Cross-sectional logistic regression analyses indicated that correlates of trying smokeless tobacco among the seventh-grade cohorts or among these same cohorts in the eighth grade (considering those persons who had not tried smokeless tobacco in seventh grade) generally included being white, trying cigarettes, risk-taking, and attending parties. Prospective logistic regression analyses with data from subjects who had not tried smokeless tobacco in the seventh grade indicated that predictors of subsequent trial of it generally included only being white and having tried cigarettes. Sports participation predicted onset only in one cohort of female subjects but not in males. Some activities that have been proposed as being predictive of smokeless tobacco use (e.g., sports participation) are generally irrelevant for a large sample of young adolescents in urban Los Angeles. White male cigarette smokers, regardless of the activities they have engaged in, are most likely to try smokeless tobacco.     

Mutual relationship among cytosolic pH, Na+ and Ca2+ ions in the degranulation of rat leukemic basophils

Reagents which affect the cytosolic concentrations of protons and sodium ions markedly affect the degranulation process of mast cells. The proton-sodium exchanging ionophore, monensin, is found to cause noncytolytic dose dependent serotonin release from the rat leukemic basophils (line RBL-2H3). Its half maximal dose of ca. 2 microM leads to secretion of ca. 20% of these cells' serotonin content. Monensin induced serotonin secretion increases with external pH and decreases upon lowering external sodium ion concentrations, yet is independent on external calcium. Monitoring cytosolic pH and free Ca2+ concentrations with BCECF and quin2, respectively, shows that a rise in pHi and [Ca2+]i is caused by the ionophore. Amiloride, the blocker of cellular Na+/H+ antiporter, is found to be an effective inhibitor of antigen or monensin induced serotonin release. However, it does not by itself cause secretion. In contrast, ouabain, which inhibits the cellular Na+/K+ ATPase, does induce secretion. Cellular levels of pH, Na+ and Ca2+ ions are evidently linked and involve a manifold of activities. Though exchanging protons for sodium seems to be effective in causing mediator release, the present results do not provide sufficient support for proton/sodium ions having a second messenger role in the immunologically induced mediator release.     

A paradigm for single nucleotide polymorphism analysis: the case of the acetylcholinesterase gene

Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. It is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goal of the present study was to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene. To this end, the genomic coding sequences for acetylcholinesterase of 96 unrelated control individuals from three distinct ethnic groups were analyzed. A total of 13 ACHE SNPs were identified, 10 of which are newly described, and five that should produce amino acid substitutions [c.101G>A (p.Arg34Gln), c.169G>A (p.Gly57Arg), c.1031A>G (p.Glu344Gly), c.1057C>A (p.His353Asn), and c.1775C>G (p.Pro592Arg)]. Population frequencies of 11 of the 13 SNPs were established in four different populations: African Americans, Ashkenazi Jews, Sephardic Jews, and Israeli Arabs; 15 haplotypes and five ethnospecific alleles were identified. The low number of SNPs identified until now in the ACHE gene is ascribed to technical hurdles arising from the high GC content and the presence of numerous repeat sequences, and does not reflect its intrinsic heterozygosity. Among the SNPs resulting in an amino acid substitution, three are within the mature protein, mapping on its external surface: they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein-protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes-such as adverse drug responses to AChE inhibitors employed in treatment of Alzheimer patients and hypersensitivity to pesticides.     

Delayed pressure urticaria

Delayed pressure urticaria (DPU) is a poorly understood syndrome. We describe 17 patients with DPU. Chronic urticaria was present in 94%. All had negative challenges for immediate demographism and cold urticaria. DPU was induced with a pressure challenge on the shoulder of 15 pounds for 15 min. Average onset of pressure lesions after challenge was 6.5. Lesions were painful, not pruritic, peaked at 9 hr, and disappeared by 24 to 48 hr. Fever, chills, and/or arthralgias occurred in 78%. Positive laboratory abnormalities included leukocytosis in 20% and elevated erythrocyte sedimentation rate in 37.5%. Skin biopsies of lesions showed perivascular round cell infiltrates and negative immunofluorescence. Urticaria responded to antihistamines, but not aspirin, in 100% of patients, while pressure lesions improved with nonsteroidal anti-inflammatory drugs (NSAID), but not antihistamines, in 80% of patients. Both urticaria and DPU were controlled with prednisone, which was necessary in 87.5% of patients. A severe nonremitting course was noted in 7%, 40% had a moderate remitting course requiring intermittent prednisone, and 53% had a mild remitting disease requiring no medication or antihistamines and/or NSAID only. We conclude that DPU is more common than previously appreciated and likely involves mediators other than histamine, possibly the prostaglandin system.     

Systemic and transcardiac platelet activity in acute myocardial infarction in man: resistance to prostacyclin

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore an understanding of factors that influence platelet performance is important. This study was undertaken (1) to characterize during evolving myocardial infarction platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and (2) to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving myocardial infarction were studied. Twenty-two patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 min. In 15 patients with anterior myocardial infarction, transcardiac platelet function and response to PGI2 were studied. Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, were elevated three- and 10-fold. 6-Keto-prostaglandin F 1 alpha, the stable end product of PGI2, was less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets circulating during evolving myocardial infarction ("ischemic platelets") were hyperaggregable in response to ADP and relatively resistant to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic AMP and the cyclic AMP response to PGI2 were diminished. The platelet hyperreactivity, expressed by plasma beta-TG, platelet aggregation, and PGI2-induced inhibition of aggregation, was most intense early during infarct evolution and decreased with time. The increased platelet performance resulted in "platelet fatigue," indicated by decreased contents of beta-TG of the ischemic platelet and decreased TxA2 production in response to collagen. However, the ischemic platelet produced twice normal TxA2 in response to arachidonic acid (stimulus and substrate), demonstrating a heightened metabolic capacity. TxA2 was produced across the ischemic/infarcting compartment in 10 of 15 patients with anterior myocardial infarction. The antiplatelet effect of PGI2 was greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving myocardial infarction, characterized by a proaggregatory environment, heightened platelet reactivity in both the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequences of the data are that the patient in the acute phase of myocardial infarction may benefit from suppression of platelet function and requires significantly greater doses of PGI2 than normal subjects.(ABSTRACT TRUNCATED AT 400 WORDS)