Ornithine as a possible marker of cancer.

The nonprotein amino acid ornithine is the major source of polyamines in mammalian physiological systems. Increased urinary polyamine levels have been demonstrated in humans with varied types of cancers. The metabolism of DL-[1-14C]ornithine monohydrochloride in rats with either Walker 256 carcinoma or chemically induced methylcholanthrene tumors was studied. Following the i.p. injection of 3 muCi[14C]ornithine per 100 g body weight, the decarboxylation of ornithine-yielding 14CO2 was monitored by utilizing the vibrating reed electrometer-ionization chamber model of Davidson and Schwabe. Tumor-bearing animals showed significant increases in ornithine metabolism as compared to controls; for Walker 256 the tumor-bearing animal to control ratio rose from 1.16 to 1.78, for methylcholanthrene implants it rose from 1.19 to 1.82, and for methylcholanthrene paintings it rose from 1.00 to 2.20. With tumor regression ornithine levels of metabolism in the tumor-bearing animals returned to base line or nearly base-line levels. These results encourage us in our attempt to develop ornithine as a biological marker of cancer.

Evaluation of isradipine (PN 200-110) in mild to moderate hypertension.

The efficacy and safety of isradipine (PN 200-110), a new dihydropyridine calcium antagonist, was evaluated in 87 hypertensive patients in a placebo-controlled, double-blind, randomized multicenter trial. After a 3-week single-blind washout phase, isradipine (or matching placebo) was administered for 4 weeks, beginning at 2.5 mg b.i.d. with increments of 2.5 mg b.i.d. at weekly intervals if supine diastolic blood pressure remained greater than or equal to 90 mm Hg. At the end of 1 week average supine blood pressure in the isradipine group (n = 45) fell from a baseline of 156 +/- 13/104 +/- 4 mm Hg to 146 +/- 14/97 +/- 7 mm Hg. By week 4 blood pressure was reduced by 19/14 mm Hg compared with 4/5 mm Hg in the placebo group (P less than 0.001 between groups). Supine and standing pulse rates were slightly increased initially with isradipine therapy but returned to baseline with increasing isradipine doses. Blood pressure responses at week 4 were good or excellent (supine diastolic less than or equal to 90 mm Hg or greater than or equal to 10 mm Hg decrease from baseline) in 87% of isradipine-treated patients and in 26% of placebo-treated patients. Headache, edema, abdominal discomfort, and constipation occurred slightly more frequently in isradipine-treated patients than in placebo-treated control subjects. The results indicate that isradipine, administered as monotherapy in doses of 2.5 to 10 mg b.i.d., is safe and effective in patients with mild to moderate essential hypertension.

Comparison of acetate-1-14C metabolism in uremic and nonuremic dogs.

Acetate-1-14C was infused into six anephric uremic and six anephric nonuremic dogs during a 4-hr hemodialysis against a standard acetate containing (39.5 mM) dialysis solution. Arterial acetate (nonradioactive) levels achieved a steady state by the end of dialysis indicating that the maximum rate of acetate metabolism had not been exceeded. The mean arterial acetate level at the end of dialysis was 2.6 mM in both groups of dogs. Acetate disappearance after the cessation of dialysis followed first order kinetics with a mean half-life of 3.8 +/- 0.5 min in the uremic and 3.7 +/- 0.5 min in the nonuremic dogs. Most of the infused acetate-1-14C was metabolized to 14CO2 within 8 hr after dialysis. An average of 84 and 71% of the infused acetate-1-14C was metabolized to 14CO2 in the uremic and nonuremic dogs, respectively. Small but significant amounts of radioactivity were incorporated into lipids of plasma and other tissues. Incorporation of radioactivity into total lipids of liver, omental fat, and sciatic nerve was significantly greater in the uremic as compared to the nonuremic dogs. Incorporation of radioactivity into total lipids of heart, aorta, and plasma was the same in both groups of dogs.

Effects of grisorixin on the distribution of thallium-201 and on the oxidative metabolism in cultured myocardial cells.

Previous experiments in the dog and guinea-pig have shown that grisorixin, a monocarboxylic ionophore, can significantly increase the coronary blood flow and the myocardial uptake of 201Tl, as well as have a stimulant effect on the heart. In this study, cultures of myocardial cells were used in order to isolate the cells from the vascular and extracardiac influences so that any ionophorous effect on 201Tl could be evidenced. The effects of grisorixin on the oxidative metabolism were simultaneously studied. The technique described by Harary was used to prepare the cultures. The activity of the 14CCO2 produced by oxidation of [14C]glucose and [14C]octanoate added to the medium of culture and the intra/extracellular ratio of 201Tl concentrations (Tl i/e) were measured. In the controls (n = 8), the Tl i/e was 40 +/- 10 while it was 17 +/- 6 (p less than 0.05) in the cells that received 201Tl and grisorixin at the same time (n = 4), and 19 +/- 5 (p less than 0.05) in the flasks where 201Tl was injected after grisorixin (n = 7). A significant decrease of the [14C]octanoate oxidation was found in the flasks treated with grisorixin (n = 4, -50 +/- 16%, p less than 0.01) while the [14C]glucose oxidation was not significantly lowered (n = 3; -11 +/- 12%). The conclusion is that grisorixin decreases both the intracellular concentration of 201Tl and the fatty-acids oxidation in cultured myocardial cells. The beneficial effects previously observed in vivo were probably the consequence of the strong coronary dilatation and of an indirect stimulation.

Effect of uremia on incorporation of acetate into rat plasma and tissue lipids.

Experimental uremia was induced in rats by means of bilateral nephrectomy or bilateral ureteral ligation. Incorporation of acetate-1-14C into expired 14CO2 and into plasma and tissue lipids was studied immediately after surgery and at 48 hr, when the rats were uremic. In rats studied immediately after surgery, bilateral nephrectomy, but not bilateral ureteral ligation, significantly decreased the conversion of acetate-1-14C into expired 14CO2. In uremic rats at 48 hr, acetate-1-14C metabolism to 14CO2 was not significantly altered in either group. Plasma triglyceride concentrations and 14C-acetate incorporation into triglycerides were increased in the 48-hr uremic groups, but plasma and liver triglyceride specific radioactivities were not significantly altered. Plasma free fatty acid concentrations and incorporation of acetate into free fatty acids were lower in the 48-hr uremic groups than in controls. Plasma cholesterol concentrations and specific radioactivities were increased in these uremic groups, as were liver free cholesterol specific activities. These results suggest that increased triglyceride and cholesterol synthesis from acetate may contribute to the hypertriglyceridemia and hypercholesterolemia observed in uremic rats.

Instantaneous and continuous measurement of 14C-labeled substrate oxidation to 14CO2 by minute tissue specimens: an ionization chamber method.

The vibrating reed electrometer and ionization chamber have been adapted for the instantaneous and continuous measurement of 14C-labeled substrate oxidation to 14CO2 by minute quantities of isolated tissues. This modified technique, utilizing a "closed" circulation incubation system, is 10-50 times as sensitive as the previously described "open" circulation techniques. Substrate oxidation curves are described for human erythrocytes and polymorphonuclear leucocytes, canine parietal cells and isolated segments of the rat nephron. This apparatus should prove to be a useful tool for metabolic studies of small quantities of isolated tissue.

Combined otolaryngological and neurosurgical approach in treating sinus fractures.

Frontal sinus injury in patients with closed head trauma is significant. Fractures of the anterior and posterior table as well as injury to the nasofrontal duct system requiring exploration, and often times obliteration of the frontal sinus, are not uncommon. Some patients present with frontal sinus damage along with intracranial pathology that requires craniotomy for treatment of the intracranial problem. In these patients, the neurosurgeon typically performs a bifrontal scalp flap to expose the cranium. A bone flap that transects the superior margin of the frontal sinus is then elevated and removed. This allows direct visualization of the anterior and posterior sinus walls and both nasofrontal ducts, subsequently facilitating reduction of fractures, debridement, and obliteration or ablation, if necessary, without creating another bone flap. The surgeon gets an overall picture of the sinus without the added trauma associated with the creation of an osteoplastic flap.

Lipid metabolism in plasma, liver, and adipose tissue of rats with experimental chronic nephrotic syndrome.

Plasma, liver, and adipose tissue lipid composition and synthesis from [1-14C] acetate were studied three months following induction of nephrotic syndrome in rats by injection of antiglomerular basement membrane protein. Plasma triglyceride concentrations and specific radioactivities were elevated, and the triglycerides contained increased proportions of oleic acid. Plasma cholesterol and phospholipid concentrations were also increased, but free fatty acid levels were not. Liver triglyceride concentrations were decreased and incorporation of [1-14] acetate into liver triglycerides was also depressed below that of normal controls. Nephrotic rat liver triglycerides contained a higher proportion of oleic acid and lower arachidonic acid than did controls. Incorporation of [1-14C] acetate into adipose tissue lipids of the nephrotic rats was increased, and the proportion of palmitic acid was decreased. In the chronic nephrotic rat, the major source of the increased plasma triglycerudes may be fatty acids mobilized from adipose tissue stores.

Relationship between 201Tl uptake and oxidative metabolism in cultured myocardial cells.

The uptake of thallium-201 (201Tl) by myocardial cells in cultures was assessed in the presence of 10(-3) M potassium cyanide (KCN), an inhibitor of mitochondrial respiration, and 10(-4) M dinitrophenol (DNP), an uncoupler of oxidative phosphorylation. The cultures were incubated with 14C-glucose or 14C-octanoate, allowing the measurement of the oxidative metabolism and beta-oxidation from the production of 14CO2. The results demonstrated a moderate decrease in the ratio between the intra/extracellular concentration of 201Tl (Tl i/e) in the presence of KCN (28.9 +/- 8.1 versus 35.6 +/- 9.7 in the controls, n.s.) and no change with DNP (37.6 +/- 9.7). Glycolysis and fatty acid oxidation were lowered with KCN (-28 +/- 15 and -45 +/- 22% respectively, p less than 0.05 in both cases) and were non significantly increased with DNP (+37 +/- 23 and +10 +/- 52% respectively). These results show that 201Tl intracellular uptake is not related directly, but is not totally independent of glycolysis and fatty acid oxidation.