Since the adoption of exchange transfusion as a method in the treatment of newborn infants with severe erythroblastosis (1-3) the question of the possible toxic effects of sodium citrate added to the administered blood, to prevent coagulation, has arisen (4). In this procedure from 85 to 95% of the infant's Rh-positive erythrocytes are replaced by the donor's Rh-negative erythrocytes depending upon the volume of blood that is administered and simultaneously removed (5). In order to effectuate an exchange of 85%o, a quantity of blood equivalent to twice the infant's blood volume must be used, and for an exchange of 98%o, a quantity of blood equivalent to four times the blood volume must be used. Since the average newborn infant has a blood volume in the range of 250-300 ml. the procedure involves the use of approximately 500 ml. and approximately 1,000 ml., respectively. With the use of sodium citrate as an anticoagulant the infant receives as much as 60 to 120 ml. of a 3%o solution of sodium citrate intravenously over a period of about 1½/2 hours.In the experimental animal, the intravenous administration of large quantities of sodium citrate has been shown to produce convulsions (6). This has been ascribed to the formation of a poorly ionized calcium citrate complex which removes calcium ion from the blood stream (7-9). Despite this consideration, exchange transfusions have been successfully carried out in a large number of cases, although occasionally deaths have been reported in the very severely affected cases (10).In order to study the adjustment that the newborn makes to the physiological strains to which it is subjected when an exchange transfusion is 1 The third in a series on the mechanism controlling citric acid levels in the blood. The first two papers in this series appeared in the Journal of Clinical Investigation, Vol. 27, pages 446 and 450, 1948. 2 This paper was presented at the Washington meeting of the American Chemical Society, August 30, 1948. carried out, citric acid, calcium, phosphorus, protein and total base levels were studied before, during and after such a transfusion on a newborn with no symptoms of erythroblastosis and with apparent normal hepatic and kidney function. The newborn studied was a mongolian idiot born in normal delivery. In addition citric acid determinations were carried out on serial bloods withdrawn from eight erythroblastotic infants during exchange transfusion. 500 ml. of blood were freshly drawn from a compatible donor. To this were added 60 ml. of 3%o sodium citrate dehydratee of tri-sodium citrate). This made a total volume of 560 ml. Over a period of approximately 60 minutes 500 ml. of. this citrated blood were infused into the saphenous vein at the ankle. After 60 ml. had been infused the radial artery was cut and the blood was collected in 60 ml. portions, during the progress of the transfusion. The first 60 ml. were added without removal of blood in order to dilate the blood vessels and make the radial artery more apparent. The cells were separated by cen...

Two different activating PTH/PTH-related peptide (PTHrP) receptor mutations, H223R and T410P, were recently identified as the most likely cause of Jansen's metaphyseal chondrodysplasia. To assess the functional importance of either amino acid position in the human PTH/PTHrP receptor, H223 and T410 were individually replaced by all other amino acids. At position 223, only arginine and lysine led to agonist-independent cAMP accumulation; all other amino acid substitutions resulted in receptor mutants that lacked constitutive activity or were uninformative due to poor cell surface expression. In contrast, most amino acid substitutions at position 410 conferred constitutive cAMP accumulation and affected PTH/PTHrP receptor expression not at all or only mildly. Mutations corresponding to the H223R or T410P exchange in the human PTH/PTHrP receptor also led to constitutive activity when introduced into the opossum receptor homolog, but showed little or no change in basal cAMP accumulation when introduced into the rat PTH/PTHrP receptor. The PTH/PTHrP receptor residues mutated in Jansen's disease are conserved in all mammalian members of this family of G protein-coupled receptors. However, when the equivalent of either the H223R or the T410P mutation was introduced into several other related receptors, including the PTH2 receptor and the receptors for calcitonin, secretin, GH-releasing hormone, glucagon-like peptide I, and CRH, the resulting mutants failed to induce constitutive activity. These studies suggest that two residues in the human PTH/PTHrP receptor, 223 and 410, have critical roles in signal transduction, but with different sequence constrains.

It has been demonstrated in animal and plant tissue studies that citric acid metabolism is intimately related to carbohydrate metabolism (1-5).

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