Radiation-induced DNA damage and repair in cells of a radiosensitive human malignant glioma cell line.

The induction and repair of DNA double-strand breaks were studied in cells of two isogenic human malignant glioma cell lines which vary in their SF2 values by a factor of approximately 30. M059J cells are radiosensitive (SF2 = 0.02) and lack the p350 component of DNA-dependent protein kinase (DNA-PK); M059K cells are radioresistant (SF2 = 0.64) and express normal levels of DNA-PK. Zero integrated field gel electrophoresis and alkaline sucrose gradient experiments indicated that equivalent numbers of DNA lesions were produced by ionizing radiation in M059J and M059K cells. To compare the capacity of both lines to repair sublethal damage, the split-dose recovery experiment after exposure to equitoxic doses of radiation was carried out. Significant sublethal damage repair was shown for M059K cells, with a 5.8-fold increase in relative survival peaking at 4 h, whereas M059J cells showed little repair activity. Electrophoresis studies indicated that more double-strand breaks were repaired by 30 min in M059K cells than in M059J cells. These results suggest that deficient DNA repair processes may be a major determinant of radiosensitivity in M059J cells.

Studies of the renal vasoactive systems in hyporeninemic hypoaldosteronism.

Plasma renin activity, total renin, active renin, and aldosterone were measured as well as urinary prostaglandin E2 and kallikrein in a group of patients with hyperkalemia (6.1-7.7 mEq per liter) and hyporeninemic hypoaldosteronism. Plasma renin activity and aldosterone were low and the response was markedly blunted to upright posture, and furosemide. The rise in cortisol but not aldosterone was normal following ACTH stimulation. Active renin was depressed; however, total renin was normal. Urine PGE was variable including some low values, but the mean of the group was normal (p greater than 0.1). Urine kallikrein excretion was markedly diminished and undetectable in most cases. Fludrocortisone normalized potassium but minimally increased kallikrein in the patients. The possibility exists that kallikrein deficiency in these patients may underlie the inability to generate active renin.

Use of right atrial catheter for prolonged iv support in cancer patients.

A right atrial catheter has proven to be a well-tolerated technical advance for patients requiring prolonged vascular access. It is easily inserted and suited for ambulatory maintenance by the patient. Catheters are utilized for a wide spectrum of iv medications with an acceptably low complication rate. Most significantly, the infection rate is negligible, despite severely compromised hosts. Their use should be considered for any patient in whom problems with vascular access are anticipated. This report comprises our experience with the first 70 catheters in 66 patients in the Hematology/Oncology service.

Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease.

Prostaglandins may modulate renal function and play a role in the hyperreninism and angiotensin pressor resistance of chronic liver disease. To study this possibility, we evaluated 12 patients with alcoholic cirrhosis and ascites. Urine immunoassayable prostaglandin E in 5 female patients was 3.3 +/- 0.5 micrograms/day [normal, 0.3 +/- 0.1 (SE)], renin was 14.6 +/- 3.7 ng/ml.h, and aldosterone was 76 +/- 19 ng/dl. After either indomethacin (200 mg) or ibuprofen (2000 mg) for 1 day, urine immunoassayable prostaglandin E fell to 0.8 +/- 0.4 micrograms/day, renin to 8.0 +/- 2.4 ng/mol.h, and aldosterone to 54 +/- 14 ng/dl (all P less than 0.01). Pressor sensitivity increased dramatically, and creatinine clearance transiently fell from 73 +/- 10 to 32 +/- 7 cc/min (P less than 0.01). Because a primary effect on renin might explain the renal impairment, an additional study used propranolol to lower renin activity. Renal function was unaltered by propranolol. We conclude that prostaglandins play a supportive role in maintaining renal function and are involved in the hyperreninism and pressor resistance of patients with liver disease.

Renal prostaglandins and sodium balance in normal man.

We investigated the relationship between urinary prostaglandin E (PGE) excretion and sodium and water balance. PGE excretion was measured in thirteen healthy male volunteers on the metabolic ward during conditions of high sodium (200 mmols/day) and low sodium diets (40 mmols/day) and during intravenous administration of saline and of dextrose and water, using each subject as his own control. PGE excretion was higher on the high sodium than on the low sodium diet (191 +/- 37 SE versus 98 +/- 41 ng/6h, p less than 0.01). Saline and dextrose and water infusions significantly increased PGE excretion while subjects were on low sodium diets (to 314 +/- 74 and 443 +/- 152 ng/6h, respectively, p less than 0.01). While on high sodium diets the increase in PGE excretion during infusions was not significant. To further evaluate the role of prostaglandin in sodium excretion the study was repeated with simultaneous administration of indomethacin or ibuprofen to inhibit prostaglandin synthesis. Sodium excretion from saline and dextrose and water infusions were unaltered. The data suggest that dietary content of sodium may alter PGE excretion, but that acute changes in PGE excretion during saline administration reflect water balance rather than sodium load.

Release of immunoassayable prostaglandin E by the human ischemic kidney.

Immunoassayable prostaglandin E concentration in renal venous plasma was measured in eight patients with renovascular hypertension. Two subjects with bilateral renal artery stenosis had similar concentrations from both renal veins. The six subjects with unilateral artery stenosis had greater concentration on the stenotic side in each case, suggesting that the human ischemic kidney produces increased amounts of prostaglandins.

Continuous intravenous deferoxamine infusion. Treatment of secondary hemochromatosis in adults.

Adult patients with chronic iron overload were given oral ascorbic acid and continuous intravenous infusions of deferoxamine mesylate. The dosage of deferoxamine mesylate was altered every 48 hours from 1 g/sq m/24 hr to 2 or 4 g/sq m/24 hr. The average iron mobilization was 55.6 mg per day at the 1 g/sq m/24 hr dosage level, 78.6 mg every 24 hours at the 2 g/sq m/24 hr dosage level, and 90.1 mg every 24 hours at the 4 g/sq m/24 hr dosage level. Iron mobilization was undiminished when successive 14-day courses of deferoxamine separated by six-week intervals were administered.

[Increased renal prostaglandin E2 secretion in Bartter's syndrome]. / Erhöhte renale Prostaglandin-E2-Sekretion bei Bartter-Syndrom.

In a 52-year-old patient with Bartter's syndrome, peripheral venous prostaglandin E2 (PGE2) and plasma renin activity (PRA) levels were markedly elevated and plasma aldosterone concentration (pa) was at the upper limit of normal, though inappropriately high relative to the decreased plasma and whole body potassium levels. Blood pressure, plasma volume, exchangeable body sodium, plasma cortisol and urinary catecholamines were normal. Renal venous PGE2 was two to three times higher than peripheral PGE2. Indomethacin (300 mg/day) decreased peripheral PGE2 by 50%, PRA by 84% and PA by 72%, induced a positive potassium balance (greater than 350 mEq) with normal plasma potassium levels, and returned the previously marked resistance to the pressor effect of angiotensin II to normal. During the entire study, highly significant correlations (p less than 0.001) between peripheral PGE2 and PRA (r = 0.86) or PA (r = 0.90) were found. In this patient the hyperreninemia was not related to volume depletion. These data indicate that in Bartter's syndrome renal PGE2 secretion may be increased, systemic blood levels of PGE2 may be elevated and closely related to PRA, and indomethacin ameliorates these abnormalities and improves potassium balance. These results are consistent with the ascription of an important role to excessive renal PGE2 secretion in the pathogenesis of Bartter's syndrome.

The effect of ACTH and cortisol on aldosterone and cortisol clearance and distribution in plasma and whole blood.

The mechanisms of increased aldosterone and cortisol metabolic clearance rates (MCR) following ACTH or cortisol administration were studied in 13 subjects undergoing cardiac catheterization and in 9 healthy controls. In control subjects, the MCR (plasma) of both steroids increased by 29% (aldosterone: from 936 +/- 57 to 1204 +/- 55 l/day/m2, cortisol: from 205 +/- 12 to 264 +/- 17 l/day/m2 +/- SE) after ACTH (12 units/h) for 1 to 4 h, and by 20 and 32%, respectively, after cortisol (12 mg/h) for 1 to 2 h. In contrast, aldosterone MCR (whole blood) did not change with ACTH or cortisol administration (from 1276 +/- 57 to 1330 +/- 59 l/day/m2), indicating that the plasma MCR increase results from a redistribution of aldosterone from plasma to red cells. Aldosterone splanchnic extraction was 92 +/- 1% (n = 12) with normal morning cortisol levels, and extraction was unchanged after ACTH administration. For cortisol, however, the splanchnic extraction increased from 8 +/- 0.8% to 17.8 +/- 5.0%, and the MCR (whole blood) likewise increased by 15 to 31% (from 295 +/- 23 to 357 +/- 30 l/day/m2), after ACTH or cortisol administration. In vivo and in vitro measurements (at 37 C) of tracer aldosterone concentration in plasma and in red cells showed an increase in distribution to red cells with increasing cortisol concentrations. The results suggest that a fraction of aldosterone is bound in plasma and displaced by cortisol into red cells. There is an increased aldosterone plasma MCR, but unaltered whole blood MCR, since the liver extracts aldosterone almost completely from both plasma and red cells. The increase in cortisol MCR (plasma) results from both an increased splanchnic extraction as plasma binding sites approach saturation and a redistribution into red cells.

The effect of prostaglandin A1 on renin and aldosterone in man.

Blood pressure, pulse rate, plasma aldosterone (PA), renin, and cortisol were monitored during graded intravenous infusions of prostaglandin At (PGA)1), 0.075-0.6 mug/kg min-1, alone and superimposed on angiotensin II (A II) administration in five normal men. The infusions of PGA1 did not affect blood pressure, but did progressively increase the pulse rate up to 15.2 +/- 2.0 (SEM- beats/min at the highest prostaglandin dose (0.6 mug/kg min-1). Both PA and plasma renin activity (PRA) increased in a dose-related fashion in response to the prostaglandin infusions. Aldosterone increased from a control of 4.8 +/- 0.4 to 20.7 +/- 1.2 ng and PRA increased from 0.9 +/- 0.1 to 5.4 +/- 0.4 ng/ml hr-1 at the dose of 0.6 mug/kg min-1. The correlation between the aldosterone and renin values was r = 0.85 P less than 0.001. In separate experiments, acute volume expansion with 2 liters of saline did not affect the increase in renin activity induced by exogenous prostaglandin. A II (5 ng/kg min-1) increased aldosterone and blood pressure and decreased the pulse rate. The hemodynamic effects were progressively reversed by the superimposed prostaglandin infusions, but the observed changes in renin and aldosterone concentrations were not further altered. The PA response to A II infusions was not influenced by indomethacin pretreatment. Prostaglandin A (infusion) appears to have a direct effect on renin release in man.