Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects.

Several studies suggest that dietary supplementation with antioxidants can influence the response to chemotherapy as well as the development of adverse side effects that results from treatment with antineoplastic agents. Administration of antineoplastic agents results in oxidative stress, i.e., the production of free radicals and other reactive oxygen species (ROS). Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and mutagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented by antioxidants, and agents that interfere with these side effects may also interfere with the anticancer effects of chemotherapy.

Development of a criteria-based performance appraisal for emergency department staff nurses.

Developing a criteria-based performance appraisal tool is a rewarding effort, but not one to be taken lightly. It took weeks. At times, the project loomed as "mission impossible." A reflection of its success is the fact that other ED staff members (e.g., charge nurses, clerks, triageurs, and lab assistants) now want criteria-based performance appraisals for their positions. We have just finished a job description and criteria-based appraisal for laboratory assistants.

Porcine cerebroside sulfate activator: further structural characterization and disulfide identification.

Cerebroside sulfate activator (CS-Act) is a small compact protein which binds and solubilizes certain glycosphingolipids. Following the recent publication of the purification and preliminary sequence of pig kidney CS-Act [Fluharty, A.L., Katona, Z., Meek, W.E., Frei, K., & Fowler, A.V. (1992) Biochem. Med. Metab. Biol. 47, 66-85], we now report the primary sequence of the C-terminal portion of this protein and the assignment of the three disulfide bonds. Cyanogen bromide (CNBr) treatment of native CS-Act produced three major and several minor peptide fragments. Analysis of one HPLC-purified fragment revealed the C-terminus 14 amino acid sequence. This established the length of the native protein at 79 residues. In conjunction with the sequence data for one other major HPLC-purified CNBr fragment, it could be concluded that the three intrachain disulfide bonds were located at half-cystine residues 4 and 77, 7 and 71, and 36 and 47. Mass spectrometry (fast atom bombardment and electrospray ionization) showed the molecular weight of the major component of the CS-Act preparation to be 9720.5 Da, which was in close agreement with the calculated mass of the 79 amino acid peptide with five covalently attached sugar residues and three internal disulfide bonds. The mass spectrometric molecular weight measurements also showed that the CS-Act preparation possessed microheterogeneity in its carbohydrate moiety, as less intense signals corresponded to species containing (in decreasing order of abundance) two, one, four, and three sugar residues.(ABSTRACT TRUNCATED AT 250 WORDS)

Postinsertional processing of sucrase-alpha-dextrinase precursor to authentic subunits: multiple step cleavage by trypsin.

Sucrase-alpha-dextrinase, a hybrid digestive carbohydrase of the intestinal brush border, is initially synthesized and transported to the surface membrane as a single-chain glycoprotein, P, which is then cleaved to alpha- and beta-subunits, presumably by one or more pancreatic proteases. However, efforts to convert P under controlled conditions to authentic alpha and beta have been unsuccessful. Sucrase-dextrinase immunoprecipitates from rats intraintestinally labeled with [3H]leucine or [35S]methionine without presence of biliary-pancreatic secretions revealed only the 230-kDa P precursor. Restoration of intestinal flow converted the brush border P to the alpha- (140 kDa) and beta- (125 kDa) subunits. Biliary plus pancreatic secretions facilitated this postinsertional cleavage, but bile alone played no role in conversion. When isolated brush borders, prelabeled in vivo, were exposed to a mixture of pancreatic proteases at physiological concentrations, P was converted to authentic alpha and beta, but only trypsin was responsible for the conversion. Kinetic analysis in prelabeled isolated brush-border vesicles revealed the appearance of several intermediate species (205-145 kDa) produced either by endogenous membrane proteases or by trypsin itself. Reconstituted duodenal luminal contents yielded a fragmentation pattern identical to that produced by trypsin alone. Trypsin was necessary and sufficient for processing of the intermediate precursors to the final authentic alpha- and beta-subunits. Based on the alpha- to beta radioactivity ratio and the known amino acid composition of the subunits, differential cleavage occurred with relatively greater production of the beta-subunit (alpha-to-beta molar ratio = 0.77). The conversion of P to the alpha- and beta-units, rather than occurring in a single step after membrane insertion, is differentially catalyzed by trypsin trimming to unequal amounts of the subunits involving a complex series of cleavage steps.

Structural and functional correlates of sucrase-alpha-dextrinase in intact brush border membranes.

The structure and catalytic function of rat intestinal sucrase-alpha-dextrinase (sucrase-isomaltase) were characterized in intact brush border membranes by differential denaturation in 1% SDS at 4, 37, 45, 55, and 100 degrees C, analysis by acrylamide electrophoresis, and subsequent renaturation by transfer to nitrocellulose and in situ analyses of immunoactivity and catalytic activity (immunoblotting and catalytic blotting). Both the sucrase and alpha-dextrinase activities were associated with two mature oligomers, with sucrase predominantly in a 250-260-kDa unit and dextrinase in a 330-350-kDa unit. While sucrase activity declined progressively in response to increasing temperature to 45 degrees C due to loss of active sites, alpha-dextrinase activity increased reciprocally (Vmax +176%). Three principal monomeric products of postinsertional processing comprise the oligomers: alpha, 140 kDa, which carries the sucrase active site; beta, 125 kDa, harboring the dextrinase active site; and gamma, 110 kDa, produced by removal of 185 amino acid residues from the N-terminus of the alpha. Rather than being a simple hybrid dimer, membrane-associated sucrase-alpha-dextrinase appears to consist of two major oligomeric forms having complex structural associations that dramatically affect the availability of the active catalytic sites at the brush border membrane surface.

Does the administration of oral Bicitra before elective cesarean section affect the incidence of nausea and vomiting in the parturient?

Soluble oral antacids are commonly used before anesthesia for cesarean section. The purpose of this prospective, single institution, randomized experimental study was to examine the relationship of oral administration of Bicitra (sodium citrate and citric acid) to the incidence of nausea and vomiting in patients undergoing elective cesarean section utilizing regional anesthesia, and to evaluate its effectiveness in neutralizing gastric acid. Eighty-six patients were studied (39 in a control group and 47 in a Bicitra treatment group) to ascertain if there was any difference with regard to height, weight, parity, gravity, age, race, incidence of heartburn with pregnancy, incidence of nausea with pregnancy, length of NPO status, preoperative systolic blood pressure (SBP), perioperative low level of SBP, and cumulative drop in SBP. Pearson chi square analysis showed no significant difference between the two groups for all variables or the incidence of nausea and vomiting. No significant difference was noted in the mean pH and volume of emesis of seven subjects analyzed using pooled t tests. After initial hypothesis testing was concluded, the sample was divided into two groups, those who experienced nausea and those who were free from nausea. The nausea group demonstrated a significantly greater cumulative decrease in SBP than did the non-nausea group. Larger patients (mean cube root weight index of 2.78) tended to become nauseated more frequently.

Effects of verapamil on uterine blood flow and maternal cardiovascular function in the awake pregnant ewe.

Calcium entry blocking drugs may have a role in the treatment of maternal and fetal tachyarrhythmias, as well as for treatment of premature labor. This study was undertaken to assess the hemodynamic effects of verapamil in the awake pregnant ewe. Verapamil, 0.2 mg/kg administered intravenously over 3 min, resulted in the following maternal cardiovascular changes: transient (2 min) but significant decreases in systolic, diastolic, and mean blood pressures, and significant but equally transient increases in central venous pressure and mean pulmonary arterial pressure. Pulmonary capillary wedge pressure increased for 5 min. These results are consistent with the negative inotropic and peripheral vasodilating effects of verapamil. Cardiac output, systemic vascular resistance, and pulmonary vascular resistance were unaffected. Uterine blood flow decreased 25% at 2 min and remained significantly (7-18%) below control levels for 30 min after drug injection. The effects of verapamil on uterine blood flow suggest that it should be used with caution in cases where uteroplacental perfusion is compromised.

Verapamil: placental transfer and effects on maternal and fetal hemodynamics and atrioventricular conduction in the pregnant ewe.

Verapamil may have application in the field of obstetrics for treatment of maternal and fetal tachyarrhythmias. This study was performed to assess the maternal and fetal hemodynamic effects of this drug, as well as to determine its placental transfer and effects on maternal and fetal atrioventricular conduction in the pregnant ewe. Verapamil, 0.2 mg/kg, administered intravenously over 3 min, resulted in a transient decrease in maternal mean and diastolic blood pressures. There was, however, no significant change in fetal systolic, diastolic, and mean blood pressures. Maternal and fetal heart rates also were unchanged throughout the experiment. Atrioventricular conduction, assessed by measurement of PR intervals, was prolonged in both the ewe (41%) and the fetus (78%). Placental transfer of verapamil was limited, as shown by the umbilical vein to uterine artery drug concentration ratios of 0.35-0.45 throughout most of the experiment. Fetal hepatic extraction of the drug appeared to be substantial, since the drug concentration in the fetal carotid artery was less than that of the umbilical vein at 1, 3, and 5 min after drug injection.

Anaesthesia for caesarean section and cerebral aneurysm clipping.

A pregnant patient at 38 weeks gestation presented for a combined procedure of Caesarean section, tubal ligation and cerebral aneurysm clipping. Anaesthesia was induced with thiopental, succinylcholine was administered to facilitate tracheal intubation, and intravenous lidocaine and sodium nitroprusside were used to reduce the hypertensive response to tracheal intubation. Anaesthesia was maintained with nitrous oxide until delivery of the infant, after which time fentanyl, low-dose halothane and pancuronium were added for maintenance of anaesthesia during the neurosurgical procedure. Blood pressure was controlled during the case by administration of a sodium nitroprusside infusion and propranolol. Following completion of the surgical procedures, the patient promptly emerged from anaesthesia and was neurologically normal in the operating room. It is concluded that general anaesthesia can be used satisfactorily for a combined procedure of Caesarean section and cerebral aneurysm clipping.

Halothane effects on ATP content and uridine uptake and phosphorylation in Tetrahymena pyriformis.

The effects of halothane on uptake and phosphorylation of uridine, and on cellular ATP content were studied in Tetrahymena pyriformis, a ciliate protozoan. Exposure to halothane inhibited the accumulation of 14C-uridine into the following acid-soluble intracellular pools: UTP, UDP, UMP, and an unidentified compound. Halothane did not alter ATP content of intact cells. It is concluded that inhibition by halothane of uridine incorporation into RNA of T. pyriformis is due to effects on uridine uptake and/or phosphorylation and not due to inhibition of the RNA polymerase reaction or reduction of ATP content.

Atropine and glycopyrrolate: hemodynamic effects and placental transfer in the pregnant ewe.

Atropine administration in pregnant women may cause fetal tachycardia and a decrease in beat-to-beat variability of the fetal heart rate. In the present study, placental transfer and maternal and fetal hemodynamic effects of atropine and glycopyrrolate were compared in chronically and in acutely instrumented, unanesthetized pregnant ewes. Administration of either atropine (0.05 mg/kg) or glycopyrrolate (0.025 mg/kg) increased maternal heart rate by 25% without changing maternal arterial pressure, fetal arterial pressure, fetal heart rate, or beat-to-beat variability. Maternal and fetal blood gas tensions also did not change. Placental transfer or atropine was significantly greater than that of glycopyrrolate throughout the entire experimental period. The peak fetal/maternal ratios observed 4 hours after injection were 1.0 for atropine and 0.13 for glycopyrrolate. On the basis of placental transfer data only, it is possible to postulate that the use of glycopyrrolate may be preferable to atropine. However, in view of the absence of circulatory effects in the fetal lamb after either atropine or glycopyrrolate, it was concluded that neither agent is preferable to the other insofar as fetal effects are concerned during ovine pregnancy. Whether these conclusions can be applied to human pregnancy remains to be determined.

Midazolam and diazepam: maternal and fetal effects in the pregnant ewe.

Maternal and fetal hemodynamic effects and placental transfer of midazolam (RO 21-3981, Hoffman-LaRoche) and diazepam were studied in chronically instrumented pregnant ewes. Diazepam administration resulted in greater increases of maternal and fetal heart rates and maternal blood pressure, and greater alteration of total uterine blood flow than did administration of comparable doses of midazolam. Neither drug altered fetal mean arterial pressure or maternal and fetal respiratory gases. Although the absolute blood concentrations were higher, the fetal:maternal drug concentration ratios were consistently less for midazolam than for diazepam, suggesting less placental permeability of midazolam.