Thomas Campbell Butler, at 63 years of age, is completing the first year of a 2-year sentence in federal prison, following an investigation and trial that was initiated after he voluntarily reported that he believed vials containing Yersinia pestis were missing from his laboratory at Texas Tech University. We take this opportunity to remind the infectious diseases community of the plight of our esteemed colleague, whose career and family have, as a result of his efforts to protect us from infection by this organism, paid a price from which they will never recover.

INTRODUCTION The probability that clinical cholera results from the interaction of a toxin produced by Vibrio cholerae with the intestine was proposed by Koch (59) and by other early investigators of the disease. Many subsequent studies support this conclusion. The nature of this toxin and its mode of action, however, remained obscure until recent years when the development of animal models closely resembling human cholera and purification of the diarrheagenic product of V. cholerae have permitted major advances in our understanding of the toxin and its mechanism of action. V. cholerae produces a number of enzymes and other products which have at times been implicated as participating in the diarrheaproducing process (9). These have been described in recent reviews (10, 11) and will not be considered here. This review will deal only with the diarrhea-producing moieties recently isolated in various degrees of purity by several investigators. These have been referred to as choleragen (34), skin permeability factor (73), vascular permeability factor (18), type-2 cholera toxin (16), cholera enterotoxin, and cholera exotoxin. Although different techniques have been employed to prepare and isolate these agents, the weight of present evidence strongly suggests that they contain the same diarrheagenic enterotoxin and that this enterotoxin is responsible for the production of the clinical cholera syndrome. In this review we have elected to employ the term cholera enterotoxin to describe this agent because its most important clinical effect is on the gut.

Antitoxic Immunity to Cholera in Isolated Perfused Canine Ileal Segments Get access George T. CurIin, George T. CurIin From the Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles C. J. Carpenter, Jr. Charles C. J. Carpenter, Jr. From the Department of Medicine, Johns Hopkins Hospital, Baltimore, Maryland Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 121, Issue Supplement, May 1970, Pages S132–S136, https://doi.org/10.1093/infdis/121.Supplement.S132 Published: 01 May 1970

Journal Article Antitoxic Immunity in Experimental Canine Cholera Get access George T. Curlin, George T. Curlin Search for other works by this author on: Oxford Academic PubMed Google Scholar John P. Craig, John P. Craig Search for other works by this author on: Oxford Academic PubMed Google Scholar Anastacio Subong, Anastacio Subong Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles C. J. Carpenter Charles C. J. Carpenter Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 121, Issue 5, May 1970, Pages 463–470, https://doi.org/10.1093/infdis/121.5.463 Published: 01 May 1970 Article history Received: 24 April 1969 Revision received: 20 November 1969 Published: 01 May 1970

Experimental Canine Cholera II. Production by Cell-free Culture Filtrates of Vibrio cholerae Get access R. Bradley Sack, R. Bradley Sack From the Department of Medicine, Johns Hopkins Hospital, Baltimore, Marvland 21205 Search for other works by this author on: Oxford Academic PubMed Google Scholar Charles C. J. Carpenter Charles C. J. Carpenter From the Department of Medicine, Johns Hopkins Hospital, Baltimore, Marvland 21205 Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 119, Issue 2, February 1969, Pages 150–157, https://doi.org/10.1093/infdis/119.2.150 Published: 01 February 1969 Article history Received: 05 August 1968 Published: 01 February 1969

In response to intraluminal challenge with crude cholera exotoxin, canine Thiry-Vella duodenal loops consistently produced isotonic fluid for a 24-36 hr period. Isotonic fluid production generally began within 15 min after challenge. Mean bicarbonate concentration of fluid produced by duodenal loops was 24+/-6 (SD) mEq/liter. Perfusion of exotoxin-treated duodenal loops with an isotonic electrolyte solution containing glucose 60 mOsm/liter caused a significant decrease in exotoxin-induced isotonic fluid output. The net effects of glucose on isotonic fluid absorption by perfused duodenal loops were not significantly different before and after administration of crude cholera exotoxin. The response of canine duodenal loops to challenge by cholera exotoxin differs from responses of jejunal and ileal loops in a) absence of a detectable "lag period" between administration of exotoxin and initiation of net fluid output; b) a longer period of fluid production following exotoxin administration; and c) a significantly greater net fluid output per unit length of gut. The mean bicarbonate concentration of the fluid produced by duodenum is less than that produced by ileum, but is not significantly different from that produced by jejunum. The duodenal response is similar to that of the more distal small bowel segments in that an effect on isotonic fluid movement is observed shortly after exotoxin administration and the maximum rate of exotoxin-induced isotonic fluid production is not reached until 4-5 hr after exotoxin administration. The basis for the consistent delay of 4-5 hr between intraluminal exotoxin administration and maximum gut fluid production has not yet been determined. Current data are consistent with the hypothesis that the rate of secretion of isotonic fluid induced by cholera exotoxin is not significantly different per unit length, in duodenum and ileum and that the lesser net fluid output in the ileum is due to the greater capacity for isotonic fluid absorption by the more distal small bowel segment.

Evidence is presented for an extra-adrenal factor which is necessary for aldosterone or DCA to produce chronic renal Na retention. To study this factor, the left kidney was transplanted to the neck, both adrenal glands and the right kidney were removed and the thoracic inferior vena cava was constricted in six dogs. For a period of two to three weeks, injection of 25 mg/day of DCA resulted in marked Na retention by the transplanted kidney and ascites formed. Neither renal venous hypertension nor the renal nerves were essential for renal Na retention under these circumstances since the transplanted kidney was denervated and its venous drainage was into the external jugular vein with a normal venous pressure. Removal of the caval ligature in four of the dogs was followed by a diuresis and loss of ascites in spite of continued injection of 25 mg/day of DCA. Similar changes occurred during the injection of aldosterone instead of DCA. Measurements of renal hemodynamic function, first, during Na retention and ascites formation and, later, after removal of the caval ligature showed levels of GFR and RPF during Na retention as high as or higher than those observed during the diuresis and subsequent Na balance. In three hypophysectomized dogs with a very low GFR and RPF, Na retention failed to occur during injection of 25 mg/day of DCA. Also, in three adrenalectomized dogs, administration of a large dose of DCA failed to produce chronic Na retention. Finally, four dogs with a large aortic-caval fistula were given 25 mg/day of DCA; sustained Na retention occurred in all four animals and ascites developed in two of the four dogs. A low rate of Na excretion in these animals was present despite a large postprandial rise in GFR. Available evidence indicates that the extra-adrenal factor is either 1) a humoral agent, or 2) some as yet undefined renal functional change.

In 1950 Deming and Luetscher demonstrated increased salt-retaining activity in urine from patients with congestive heart failure (1). In 1953 aldosterone was isolated (2), and subsequently the urinary excretion of this hormone was found to be elevated in nearly all the clinical states associated with edema. Two possible mechanisms could lead to an increase in the plasma level of aldosterone and thus to an increase in urinary aldosterone excretion: 1) hypersecretion of aldosterone, and 2) a decreased rate of metabolism of the hormone. In 1957, it was demonstrated that a sixfold increase in aldosterone secretion occurred in dogs with experimental right heart failure and in dogs with thoracic inferior vena caval constriction (3). The possibility of decreased metabolism of aldosterone was suggested by Yates, Urquhart and Herbst (4) who found a decrease in the 4,5-steroid reductase activity for inactivation of aldosterone by liver tissue from rats subjected to chronic passive venous congestion. They suggested that a decreased rate of reduction of ring A of aldosterone might increase the plasmal level of the hormone in these animals. The primary purpose of the present study was to evaluate the possibility of a decreased rate of metabolism of aldosterone by the congested liver. The disappearance of H3aldosterone from plasma was studied in dogs with chronic hepatic venous congestion secondary to thoracic inferior vena caval constriction and in normal animals. In addition, several aspects of the metabolism of dl-aldosterone were studied including the urinary and biliary excretion of

Following midbrain transection of six normal dogs, secretion rates for aldosterone, corticosterone and Porter-Silber chromogens were not significantly different from values obtained in unoperated dogs; subsequent bleeding increased aldosterone secretion while corticosterone output was unaltered. In five dogs with thoracic caval constriction in which there was a high secretion of aldosterone, midbrain transection was followed by a reduction in inferior vena caval pressure to a level which was apparently too low to sustain the mechanisms resulting in hyperaldosteronism. In one animal aldosterone and corticosterone output was extremely low despite a high venous pressure. In the two dogs with caval constriction in which the venous pressure remained elevated after midbrain transection, the high rate of aldosterone secretion persisted. Bleeding of dogs with caval constriction and midbrain transection resulted in a striking increase in aldosterone secretion. In dogs with caval constriction, corticosterone secretion (5 dogs) and Porter-Silber chromogen output (4 dogs) were high following midbrain transection, and subsequent bleeding failed to increase corticosterone output. It is concluded that complete midbrain transection does not interfere with the high rate of aldosterone secretion which occurs in response to acute blood loss or following caval constriction if venous pressure is maintained at the high control level.