Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis

Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized "good-risk" patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the "good-risk" children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for "good-risk" patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.     

Glutathione peroxidase (GPX) activity in seminal plasma of healthy and infertile males

Human spermatozoa are more dependent on glutathione peroxidase/glutathione reductase (GPX/GR) system, via reduced glutathione (GSH), to inactivate reactive oxygen metabolites (ROMs) such as hydrogen peroxide and organic hydroperoxides. To demonstrate whether there is a substantial difference in GPX activity between normal and pathological seminal plasma, we decided to evaluate the activity of this enzyme in healthy subjects and infertile males with normal hormonal patterns. Our results demonstrate that in healthy subjects the seminal plasma contains a GPX activity that is about 10 times greater than the GPX activity detected in the seminal plasma of infertile males. By using specific antibodies against plasmatic GPX (GPX3), we also demonstrate that enzymatic activity, detected in the seminal plasma of both healthy and infertile males is GPX3. Therefore, the evaluation of GPX activity in human seminal plasma could be a new useful marker of gonadal function in men.     

Nail involvement in osteoarthritis

Summary Two cases of nail involvement associated with primary interphalangeal osteoarthritis of the hand, including leukonychia and longitudinal nail ridge, are reported. Osteoarthritic changes of the distal interphalangeal joints may cause nail lesions by exerting direct pressure on the nail matrix or by interfering with local blood flow. Moreover, inflammation of the Heberden's nodes is often present and seems to participate in the development of nail alteration. In our patients, leukonychia disappeared after local steroidal anti-inflammatory treatment of the osteoarthritic node and longitudinal nail ridge disappeared after treatment with nonsteroidal anti-inflammatory agents.     

A Comparison of the Hemodynamic Effects of Inotropic Agents

This experimental study was conducted to compare and contrast the cardiovascular effects of the drugs most commonly used to alleviate low-cardiac-output syndrome. Twenty-five adult mongrel dogs were infused with sodium pentobarbital (60 mg/min) until their cardiac output fell to 50 ± 5% of the average control values determined by thermodilution technique prior to pentobarbital infusion. The dogs were then divided into six groups, and one of the following agents or combinations of agents was administered to each group: isoproterenol, glucagon, dopamine, dobutamine, levarterenol and phentolamine, or levarterenol and nitroprusside.All drugs, except for glucagon and the combination of levarterenol and nitroprusside, produced an increase in cardiac output above the nonfailure baseline values. However, this increase was accompanied by an undesirable, pronounced tachycardia except when levarterenol was used simultaneously with phentolamine. Both dopamine and the combined infusion of levarterenol and phentolamine proved the most effective in restoring systemic arterial pressure to near baseline values, and both were able to increase renal blood flow above the failure baseline values. While renal blood flow remained elevated with all dosages of levarterenol and phentolamine, it tended to decrease with larger doses of dopamine.These experiments demonstrate that there are major advantages in the use of simultaneously infused levarterenol and phentolamine for control of low-cardiac-output syndrome: increased cardiac output without elevated peripheral vascular resistance, restoration of systemic arterial pressure and consequent improved coronary flow, absence of tachycardia, and augmented renal blood flow.     

Converting enzyme inhibition augments and competitive inhibition of angiotensin II partially restores reflex adrenal catecholamine release in anephric dogs.

Adrenal epinephrine (E) release after hemorrhage in anesthetized dogs is blunted by acute nephrectomy and restored by angiotensin II infusion. In the present study, we report the effect of converting enzyme inhibition by SQ 20881, a decapeptide, and of competition inhibition of angiotensin II by saralasin (1-Sar-8-Ala-Ang-II) on reflexly stimulated adrenal release of E and norepinephrine (NE) in three groups of acutely anephric dogs. Aortic catheters and adrenal vein to femoral vein Silastic shunts were placed in dogs anesthetized with pentobarbital and mechanically ventilated. Adrenal secretion rates were calculated from adrenal vein to aorta catecholamine concentration differences divided by measured adrenal venous flow. Catecholamine concentrations were determined with trihydroxyindole technique. Blood samples were obtained before and 15, 30, and 60 min after rapid hemorrhage to a stable mean arterial pressure of 50 mm Hg. Saralasin infusion (10 microgram/kg/min) supported adrenal E release in anephric hemorrhaged dogs toward secretion rates comparable to those seen in intact dogs. Anephric SQ 20881 (approximately 0.5 microgram/kg) recipients had delayed (60 min) augmented adrenal E and NE release after hemorrhage. In resting animals not reflexly stimulated by hypovolemia, neither drug provoked adrenal E or NE release. These results suggest an agonist effect of saralasin on reflex adrenal E release and increased responsiveness of the stimulated adrenal medulla under the influence of converting enzyme inhibition.