Intercalative binding of ellipticine to DNA.

Ellipticine (NSC 71795), a plant alkaloid with antitumor activity, is a weakly basic polycyclic molecule with dimensions similar to those of proflavin. Like proflavin, ellipticine exhibits hypocromic and bathochromic changes in absorption spectrum in the presence of DNA. It binds preferentially to helical DNA by intercalation, but the strength of binding is substantially greater than that of proflavin. The evidence for intercalation is based on effects on the sedimentation and viscosity of sheared DNA fragments, removal and reversal of the supercoiling of closed circular DNA, and electric dichroism measurements. The sedimentation and viscosity changes are quantitatively similar to those produced by proflavin. The unwinding angle on binding to supercoiled DNA is estimated to be 7.9 degrees, similar to that of proflavin. Electric dichroism shows the plane of the bound ellipticine molecule to be oriented parallel (plus or minus 7 degrees) to the plane of the bases in helical DNA. Ellipticine differs from proflavin in that it is uncharged at neutral pH and becomes protonated under mildly acid conditions. This feature may influence the intracellular distribution of the drug. Ellipticine bound to DNA is probably in its protonated form.

Rapid diagnosis of group B streptococcal infection utilizing a commercially available latex agglutination assay.

The Wellcogen Strep B latex assay rapidly identifies all cases of culture-positive sepsis and meningitis and may be more sensitive than standard culture techniques for identifying group B Streptococcus disease and assessing the degree of severity. The quantitation of antigen concentration combined with the peripheral WBC count proves helpful in predicting poor outcome.

Survival and neutrophil kinetics in infants with severe group B streptococcal disease treated with gamma globulin.

To estimate the efficacy of intravenous gamma globulin adjunct therapy on the course of severe neonatal group B streptococcal (GBS) disease, the hospital records of 67 confirmed cases of early-onset GBS sepsis associated with neutropenia were reviewed. Among the 33 infants who had received antibiotic agents without gamma globulin, 13 (39%) died. Among the 34 who had received antibiotic agents plus gamma globulin, 6 (18%) died (p < 0.05). Among 52 low birth weight infants, 5 (20%) of the 25 given gamma globulin died compared with 13 (48%) of the 27 not given gamma globulin (p < 0.03). Neutrophil counts rose more rapidly among survivors who received gamma globulin than among those who did not. This retrospective study suggests that intravenous gamma globulin adjunct therapy for neonatal GBS disease associated with neutropenia promotes a more rapid increase in neutrophil count and improves survival.

Relationship between serum inositol concentration and development of retinopathy of prematurity: a prospective study.

PURPOSE: To examine the relationship between the intake of sugar inositol, serum inositol levels, and ROP in three groups of low birthweight infants receiving feedings containing various concentrations of inositol. METHODS: Infants with a birthweight <1500 g, with severe lung disease, were eligible for the study when they began enteral feedings. Infant formulas contained three different inositol concentrations: 2500, 710, and 242 micromol/L. Serum inositol concentrations were averaged over specific time intervals. A logistic regression model was used to investigate the confounding effect of duration of mechanical ventilation and oxygen therapy, birthweight, Apgar score, and serum inositol concentration on development of ROP. RESULTS: Infants receiving high inositol formula and with higher serum inositol concentrations at birth and after 30 days had a statistically significant lower incidence of severe ROP than those receiving the lower inositol formula and with lower serum concentrations (P<.05). The effective serum inositol concentration (EC90) associated with lesser disease was >215 micromol/L. By logistic regression, the odds of developing severe ROP were greater among infants with low serum inositol concentration (odds ratio=4.7, 95% confidence interval 0.90-24.8, P=.017). CONCLUSION: Inositol supplementation may help prevent the most severe form of ROP.

Influence of T-helper cell specific monoclonal antibody on progressive growth of B-cell lymphomas in SJL/J mice: correlation of acute treatment dosage with tumor dormancy or complete remission in long-term survivors.

Transplantable follicular center cell lymphomas of SJL/J mice (SJL/FCC) are B-cell-derived tumors that stimulate host T-helper (TH) cells and grow progressively in the lymphoid tissues of immunocompetent, syngeneic recipients. The host TH cells that respond to the I-As determinants on SJL/FCC lymphoma cells produce a variety of lymphokines, some of which (e.g., IL-5) promote in vitro tumor growth. The results presented here demonstrate that removal of the cellular source of tumor growth-promoting lymphokines by treatment of lymphoma-injected mice with TH cell specific monoclonal antibodies (anti-L3T4a) inhibits progressive tumor growth and prolongs survival significantly. However, long-term survival is mediated by different mechanisms, depending on the dosage of L3T4a mAb used. Tumor cells are present, but dormant, in mice that receive low-dose (less than 200 micrograms/injection) treatment. In contrast, tumor cells are undetectable in mice that receive high dose (1200 micrograms/injection) treatment.

Chloramphenicol disposition in infants and children.

We studied the pharmacokinetics of chloramphenicol following its intravenous administration as the sodium succinate ester to 54 infants and children. The mean "apparent t 1/2" of chloramphenicol clearance from the plasma was 5.94 hours (range 0.87 to 17.8 hours). The t 1/2 of patients who weighed less than 10 kg was significantly longer than that of those who weighed more than 10 kg (9.02 vs 4.55 hours; P less than 0.0001). There was a discrepancy between the plasma levels of chloramphenicol and total aromatic nitro compounds in four patients; these compounds were cleared at different rates. Repeated dosing (eight to 30 doses) did not produce a consistent effect on the t 1/2. The CSF concentrations of chloramphenicol in 13 patients were 67% (range 45 to 99%) of the simultaneous serum concentrations. We conclude that the marked individual variation in chloramphenicol pharmacokinetics in infants and children requires monitoring of blood concentrations during therapy.

Children's use of multiple-counting skills: adaptation to task factors.

The purpose of the study was to determine conditions under which young children enumerate by counting in multiples. Thirty-eight kindergartners and first-graders enumerated dot displays and gave verbal reports of their strategies; additionally, they were given an independent assessment of multiple-counting skill. Dot displays varied according to overall numerosity, perceptual arrangement (random, clustered, rectangular), and numerosity of subgroupings. Children were relatively accurate at enumerating small-numerosity and nonrandom displays. They were relatively likely to report counting by multiples, rather than by ones, on small-numerosity and clustered displays. Contingent upon their skill level, children counted by multiple units (twos, threes, and fours) that corresponded to the numerosity of subgroupings (2, 3, and 4). Contrasting effects of different numerosities and perceptual arrangements are discussed in terms of contextual support for the use, and development, of numerical skills among young children.

Gentamicin disposition in asphyxiated newborns: relationship to mean arterial blood pressure and urine output.

The purpose of this study was to investigate the effects of changes in renal function on gentamicin disposition following perinatal asphyxia. Gentamicin pharmacokinetics, renal function, mean arterial pressure (MAP) and five-minute Apgar scores were determined in 80 preterm infants admitted to two neonatal intensive care units over an 18 month period. A 2.5 mg/kg dose of gentamicin was infused intravascularly over 20 to 30 minutes in a retrograde fashion. The gentamicin half-life and clearance were prolonged in asphyxiated infants. For the asphyxiated infants gentamicin half-life increased and urine output decreased with a significant correlation (r = -0.66, p less than 0.05). Gentamicin clearance and urine output in the asphyxia group correlated with MAP (r = +0.67, p = 0.07). In non-asphyxia infants no such correlation was seen. This study does not distinguish between asphyxia-induced or gentamicin-induced nephrotoxicity following gentamicin therapy. We suggest that gentamicin concentrations be closely monitored in asphyxiated newborns who demonstrate compromised renal function.

Fractionation of DNA from mammalian cells by alkaline elution.

The method of alkaline elution provides a sensitive measure of DNA single-strand length distribution in mamalian cells and is applicable to a variety of problems concerning DNA damage, repair, and replication. The physical basis of the elution process was studied. The kinetics of elution above the alkaline transition pH were found to occur in two phases: an initial phase in which single-strand length is rate limiting, followed by a phase in which elution is accelerated due to the accumulation of alkali-induced strand breaks. The range of DNA single-strand lengths that can be discriminated by elution above the alkaline transition pH was estimated by calibration relative to the effects of x ray, and was found to be 5 X 10(8)-10(10) daltons. Shorter DNA strands elute within the pH transition zone, which extended from pH 11.3 to 11.7 when tetrapropylammonium hydroxide was used as base. This elution was relatively rapid, but was sharply limited by pH, according to the length of the strands: the length of the strands eluted increased with increasing pH. Alkaline elution was inhibited by treatment of cells with low concentrations of nitrogen mustard, a bifunctional alkylating known to cross-link DNA. On investigation of the possibility that DNA subclasses may differ in their elution behavior, satellite L strands were found to elute more slowly from cells exposed to a low dose of x ray than did the bulk DNA.

Intravenous gamma globulin as adjunct therapy for severe group B streptococcal disease in the newborn.

Group B streptococcal (GBS) disease remains a significant cause of morbidity and mortality among newborns despite aggressive antibiotic and supportive therapy. Recent success with the prophylactic use of intravenous gamma globulin (IVIg) in newborns suggests that use of IVIg may be an additional therapy for infants with severe GBS disease. Eighty-four infants with GBS antigen in serum, urine, and in some cases spinal fluid were identified by a rapid latex agglutination assay. Twenty-four of these infants had both neutropenia and serum GBS antigen titers of 1:10 or greater and had the highest risk of dying from their infection. Before the availability of IVIg, seven of the first 12 of these infants identified with the highest risk factors died (58%). Twelve additional patients with these highest risk factors have been treated with IVIg. Two of these 12 died (17%), p less than 0.01 when compared with the previous highest risk group. In surviving patients in both IVIg-treated and non-IVIg-treated groups, the time for recovery from neutropenia was 2 to 4 days. Our study suggests a possible beneficial effect of IVIg as adjunct therapy in severe GBS disease.

Serum alpha-tocopherol concentrations in preterm infants receiving less than 25 mg/kg/day alpha-tocopherol acetate supplements.

Alpha-tocopherol (aT) concentrations were determined in 52 preterm infants receiving less than 25 mg/kg/day alpha-tocopherol acetate (aTA) supplements through intravenous hyperalimentation solutions, lipid, and oral aTA. One fourth of the study infants had aT concentrations greater than 3.5 mg/dl at least once, and an association between concentrations greater than 3.5 mg/dl and necrotizing enterocolitis was demonstrated. In contrast, another one fourth of the infants' concentrations remained less than 0.5 mg/dl through the first postnatal week. The highly variable serum tocopherol concentrations correlated with total serum lipid content but not with plasma aTA hydrolysis activity.

Indomethacin and the preterm infant with a patent ductus arteriosus: relationship between plasma concentration and ductus closure.

The relationship of indomethacin pharmacokinetics to clinical and echocardiographic evidence of closure of the patient ductus arteriosus (PDA) is described in 9 preterm infants. PDA closures occurred in 4 infants when peak indomethacin plasma concentrations were 0.71-1.10 micrograms/ml, mean 0.93 +/- 0.16 microgram/ml. With partial or no PDA response to oral treatment, the peak concentrations were 0.20-0.69 microgram/ml, mean 0.57 +/- 0.08 microgram/ml, p less than 0.01. The left atrial size in the study infants correlated inversely with the indomethacin peak concentrations, r = 0.75. The plasma apparent terminal half-life correlated with postnatal age, r = 0.75. All patients with peak concentrations greater than 0.50 microgram/ml had transient oliguria. This study suggests that a minimum indomethacin concentration may be needed to promote PDA constriction.

Metabolism and disposition of indomethacin in preterm infants.

38 preterm infants with symptomatic patent ductus arteriosus received indomethacin intravenously. Plasma samples were collected at 2, 4, 6 or 8 and 12 h after each of 3 doses. Indomethacin, demethylindomethacin and p-chlorobenzoic acid were determined in plasma and urine along with acid-labile metabolites using HPLC. Fifty-eight percent of the infants demethylated indomethacin; half of the unchanged and demethylated drug was found as conjugates in urine; 14% deacylated the drug. Shorter elimination half-life, smaller area under the plasma concentration-time curves and increased plasma clearance were associated with demethylation. Postnatal age greater than 2 weeks correlated with both demethylation and failure of indomethacin to effect ductal closure.