Renal and systemic acid-base effects of chronic dichloroacetate administration in dogs

Dichloroacetate (DCA) increases metabolic disposal of lactic acid secondary to activation of pyruvate dehydrogenase and consequent acceleration of pyruvate oxidation. DCA has thus been proposed as a therapeutic agent for clinical states of lactic acidosis. Yet, DCA has a potential metabolic acidosis-producing effect by virtue of reported effects of (A) increasing blood ketoacid concentration, (B) decreasing tubular reabsorption of filtered ketoacid anions, and (C) decreasing renal NH₃ production. In the present study chronic administration of DCA, 50 mg/kg p.o. daily for 6–8 days, resulted in a cumulative increase in renal net acid excretion (NAE) (ΣΔNAE, +61 meq, p < 0.05). The increase in NAE was accounted for entirely by increased NH₄⁺ excretion. Production of ammonia by the kidney appeared to be increased since the increased excretion of NH₄⁺ was accompanied by an increase in urine pH (ΔUpH, +0.18 ± 0.07, p < 0.05). The increase in NAE was accompanied by a nearly identical increase in urinary anion gap (UAG) (UAG = [NH₄⁺ + Na⁺ + K⁺] ? [Cl^? + HCO₃^? + HPO₄^2? + H₂PO₄^?]). The increase in UAG was caused by increased urinary total organic anions, accounted for at least in part by a significant increase in urinary acetoacetate. No significant increase in urinary potassium or sodium excretion occurred. A change in plasma acid-base composition occurred that was consistent with a mild respiratory acidosis without associated primary metabolic acidosis or alkalosis. These findings indicate that chronic DCA administration results in (1) increased steady state endogenous noncarbonic organic acid production, and (2) retention of carbonic acid. Further investigation of the potential metabolic and respiratory acidosis-producing effects of DCA is required to determine its clinical efficacy in the treatment of clinical lactic acidosis.     

Single-acquisition chemical-shift imaging of a binary system with use of stimulated echoes

A method for separating binary chemical-shift components with a single image data acquisition by means of stimulated echoes is demonstrated. With a strategy analogous to the modified Dixon method, three stimulated echoes were acquired to form three complex images. In each of the images, the complex pixel intensities were imparted, by design of the pulse sequence, with a phase factor carrying chemical-shift or field inhomogeneity information. With these three images, true fat/water separation can be obtained in biologic tissues. Studies at high field strength (4.7 T) on a toluene phantom, a pseudo-binary chemical-shift system, were used to evaluate the applicability of the method. Its clinical feasibility was demonstrated on a healthy human subject in a 0.6-T whole-body imaging system.     

Persistent Erection (Priapism) for Months with Concomitant Infertility in Rats due to Protein-Energy-Malnutrition

Monatelange Erektion (Priapismus) mit konsekutiver Infertitität bei Ratten als Folge von Protein-Energie-Mangelernährung
Wachsende, männüche Sprague Dawley Ratten wurden 22 Wochen lang mit einer halbsynthetischen, 9% Rohprotein enthaltenden Diät gefüttert, wobei Kasein (Kontrollgruppe; I) oder Weizenbrotkruste (Gruppe II) die alleinigen Proteinquellen darstellten. Das Kontrollfutter in reduzierter Menge, in Anlehnung an den Futterverzehr der Krusten-Ratten, wurde einem dritten Kollektiv verfüttert (pair-fed-Gruppe; III). Nach 6 Versuchswochen zeigten sich in den Gruppen II und III erste pathomorphologische Genitalveränderungen, die sich in einer monatelangen Erektion manifestierten. Bei 97% der Krusten-Ratten, 67% der isoenergetisch gefütterten Kasein-Ratten, jedoch bei keinem Kontrolltier entwickelte sich am Ende des Beobachtungszeitraums eine Dauererektion. Nach der 15. Versuchswoche erzielten die pair-fed-Ratten 17%, die Krusten-Ratten nur 5% des Gewichtszuwachses der Kasein-Kontrollgruppe. Im Reproduktionstest mit gesunden weibl. SD-Ratten erwies sich nur 1 von 6 Krusten-Ratten als zeugungsfähig, nach anschließender 5wöchiger ad lib. Kasein-Wiederauffütterung konnte eine 83% Fertilität beobachtet werden. Der Pathomechanismus der nutritiv induzierten Dauererektion wird auf die ausgeprägte marastische Stoffwechsellage zurückgeführt, bedarf jedoch weiterer Aufklärung.     

Neutral steroid metabolites in patients with uraemia and after renal transplantation: a quantitative and qualitative study in body fluids

Steroid metabolites enriched from urine, haemofiltrate, and CAPD-dialysate (Continuous Ambulatory Peritoneal Dialysis) were identified by gas chromatography-mass spectrometry and quantified by capillary gas chromatography. The study included twenty healthy controls, twenty-six non-dialysed uraemics, thirty-nine patients on regular dialysis treatment, and twenty-two allograft recipients. Compared to the 24 h urinary excretion rates of controls the excretion rates of androsterone and etiocholanolone were in the lower normal range up to significantly decreased in the body fluids of all patients, and those of the corticoid metabolites were also significantly decreased. 11-Oxygenated androstanolones in urine from non-dialysed uraemics correlated significantly decreased. 11-oxygenated androstano-levels and were significantly increased, but normal in haemofiltrate and CAPD-dialysate, while in urine of allograft recipients the values were significantly lower.     

Hyperlipidemia, hypercoagulability, and accelerated thrombosis: studies in congenitally hyperlipidemic rats and in rats and monkeys with induced hyperlipidemia

Inbred Carworth Farms Nelson (CFN) congenitally hyperlipidemic rats had significantly shorter coagulation and prothrombin times and higher levels of coagulation factors, II, V, VII, VIII, and X than did controls. Conversely, congenitally hypolipidemic rats of the same strain had significantly longer coagulation and prothrombin times and lower levels of factors II, V, VII, X and XII and of blood platelets than did controls. A loop-shaped polyethylene cannula was inserted into the aorta to assess the potential for thrombosis. The hyperlipidemic group obstructed this significantly faster and the hypolipidemic group slower than did the controls. Normal CFN rats made hypertensive by unilateral renal artery clip developed hypertension together with significantly elevated serum cholesterol and factor VII and X levels. Rhesus monkeys with diet-induced hyperlipidemia showed shorter prothrombin times and higher factor X levels than did controls on normal diet. By selective breeding, two groups of squirrel monkeys were obtained. Both groups had similar serum cholesterol levels on a normal diet but one group (hyperresponders) showed higher serum cholesterol levels on a cholesterol-containing diet than did the other (hyporesponder) group. Both groups showed significantly elevated levels of factors II, V, VII, IX and X on a cholesterol-containing diet. There was good correlation between the levels of many coagulation factors and serum cholesterol in both rats and monkeys. If thrombosis is important in the genesis of atherosclerosis, these findings could indicate that elevation of plasma lipids may play a role, via the coagulation pathway, in the production of human vascular disease.     

RADIOLOGIC EVALUATION OF PROPHYLAXIS IN SEVERE HAEMOPHILIA

ABSTRACT. Pettersson, H., Nilsson, I. M., Hedner, U., Noréhn, K. and Ahlberg, Å. (Department of Diagnostic Radiology, Coagulation Laboratory and Department of Orthopedics, University of Lund, Malmö General Hospital, Malmö, Sweden). Radiologic evaluation of prophylaxis in severe haemophilia. Acta Paediatr Scand, 70:565,.–The effect of prophylactic treatment of severe haemophilia A and B was evaluated with a recently described radiologic score system for assessing the severity of arthropathy. The severity of the arthropathy was assessed in 50 patients with severe haemophilia receiving prophylaxis with factor VIII or IX (25–30 units factor VIII or IX/kg bodyweight at 4–7 day intervals), and in 9 in whom the condition was complicated by inhibitors and who were thus not receiving prophylaxis. The score values found in a recent investigation of the natural course of haemophilia served as controls in the evaluation of the effect of the prophylaxis. In the group with severe haemophilia receiving prophylaxis changes appeared only exceptionally in joints not affected already before the prophylaxis, and the course of the arthropathy and its severity according to age did not vary to any noteworthy extent from that in the control group with moderate haemophilia. In the cases complicated by inhibitors the joints were most often worse than those in the control group with severe haemophilia. It is concluded that prophylaxis has a considerable effect on the course of the arthropathy and the prophylaxis should be instituted at an early stage of the disease, when the joints are still unaffected.