A limited-sampling method for evaluation of the area under the curve of ultrafilterable carboplatin in children

Carboplatin is a widely used cytotoxic agent in numerous solid tumors of children. Since there is a large degree of interpatient variability in the area under the curve of free carboplatin for a given dose of the drug, the current tendency is to adjust the carboplatin dose so as to reach a target area under the curve rather than to determine a carboplatin dose on the basis of the body surface area. A limited-sampling method was developed for estimation of the ultrafilterable carboplatin area under the curve and for adjustment of the carboplatin dose on subsequent treatments. Population parameters were obtained from 16 children (reference group). We used the maximum a posteriori (MAP) Bayesian approach on 15 children with complete carboplatin pharmacokinetic data (test group). Two blood samples were sufficient to obtain reliable prediction of the area under the curve. The best sampling times were: (a) 30 min after the end of the infusion and (b) 5 h after the end of the infusion. On the basis of these data it is possible to prescribe prospectively a target area under the curve for free carboplatin given in a fractionated daily infusion and to adapt the carboplatin dose directly to ultrafilterable carboplatin measurements. Received: 8 June 1997 / Accepted: 9 January 1998     

Childhood obesity increases duration of therapy during severe asthma exacerbations.

OBJECTIVES: Childhood obesity contributes to a wide array of medical conditions, including asthma. There is also increasing evidence in adult patients admitted to the intensive care unit (ICU) that obesity contributes to increased morbidity and to a prolonged length of stay. We hypothesized that obesity is associated with the need for increased duration of therapy in children admitted to the ICU with status asthmaticus. DESIGN: Retrospective cohort study. SETTING: A tertiary pediatric ICU in a university-affiliated children's hospital. PATIENTS: We retrospectively examined data from all children older than 2 yrs admitted to the ICU with status asthmaticus between April 1997 and June 2004. Children were classified as normal weight (<95% weight-for-age percentile) or obese (>95% weight-for-age). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 209 children admitted to the ICU with asthma, 45 (22%) were obese. Compared with children of normal weight, the obese children were older (9.7 +/- 4.4 vs. 8.0 +/- 4.3 yrs, p = .02), more likely to be female (60% vs. 37%, p < .01), and more likely to have been admitted to the ICU previously (40% vs. 20%, p = .01). The obese children also had a statistically significant difference in race (more likely to be Hispanic) and in baseline asthma classification (more likely to have persistent asthma). Despite similar severity of illness at ICU admission, obese children had a significantly longer ICU length of stay (116 +/- 125 hrs vs. 69 +/- 57 hrs, p = .02) and hospital length of stay (9.8 +/- 7.0 vs. 6.5 +/- 3.4 days, p < .01). Obese children also received longer courses of supplemental oxygen, continuous albuterol, and intravenous steroids. CONCLUSIONS: Childhood obesity significantly affects the health of children with asthma. Obese children with status asthmaticus recovered more slowly from an acute exacerbation, even after adjustment for baseline asthma severity and admission severity of illness.     

Production of herpes simplex virus type 1 thymidine kinase in the presence of thymidine analogues

Treatment of herpes simplex virus type 1 (HSV-1) infected Vero, BHK, BHKtk- and LMtk- cells with 5-iodo-5'-amino-2',5'-dideoxyuridine (AIdUrd) caused increased synthesis of ICP36 and an increase in HSV-1 thymidine kinase (tk) activity at late times of infection. The overproduced ICP36 was identified as the HSV-1 encoded tk protein by immunoprecipitation. Whereas the thymidine analogue 5'-amino-5'-deoxythymidine (AdThd) caused an increase in HSV-1 tk synthesis and activity in wild type Vero and BHK cells, 5-iodo-2'-deoxyuridine (IdUrd) caused a similar increase only in tk- cells (LMtk-, BHKtk-). In vivo and in vitro stabilization studies using a [35S]methionine pulse-chase experiment or heat inactivation studies with purified HSV-1 tk revealed that stabilization of tk by the analogues could not account for the extent of the observed increase. Since overproduction of tk is observed only at late times of infection, it is suggested that the presence of these thymidine analogues in either the viral DNA or the cellular nucleotide pools is responsible for the observed differential effects.     

LAW AND ETHICS

Abstract

As society attempts to reduce sex stereotyping, it would be expected that male and female attitudes toward death would become similar. The purpose of this study was to measure various death-related attitudes of a group of adolescents and to determine if these attitudes remain sex related.

A sample of 152 seventh, eighth, and ninth-grade males (N = 71) and females (N = 81) from a Washington, D.C., metropolitan-area junior high school completed the Likert-type instrument. Using the chi-square statistic it was found that males and females differed significantly on 11 of the 22 items on the survey. Generally, females more than males, were in favor of abortion, valued funerals, and were more concerned with what might happen to their body subsequent to death. Differences were also found in attitudes about capital punishment and life after death. However, no significant male-female differences were found in fear of death.

It was concluded that differences in attitudes toward death generally are still consistent with traditional sex roles.     

To the marriage of true minds: Some synergisms of ethics,law, and medicine

Abstract

Ethics and law have influenced the practice and the teaching of medicine. This paper traces some of that influence by examining the concepts of paternalism and privacy. Some surprising ways that philosophy has affected medicine are also detailed. What is finally revealed is the value-laden nature of medicine, ethics, and law.     

The Coagulation Mechanism in Acute Bacterial Infection

Successive coagulation studies were performed in 34 adult patients hospitalized for treatment of acute bacterial infection. Increased fibrinogen, factor-VIII activity, and platelets were found in more than 50% of the patients studied. Classical disseminated intravascular coagulation occurred in three cases. Nine patients had elevated fibrin split products in various combinations with transient hypofibrinogenaemia, thrombocytopenia, and reduced factor-V activity. The appearance of elevated fibrin split products together with transient hypofibrinogenaemia, thrombocytopenia, and reduced factor-V activity in some patients may reflect the presence of subclinical disseminated intravascular coagulation.     

Erythropoietin-specific cell cycle progression in erythroid subclones of the interleukin-3-dependent cell line 32D [published erratum appears in Blood 1993 Jun 1;81(11):3168]

Recently, a variety of growth factor-dependent subclones of the murine interleukin-3 (IL-3)-dependent cell line 32D have been isolated. These subclones include those dependent for growth on erythropoietin (Epo) (32D Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF) (32D GM), or granulocyte colony-stimulating factor (G-CSF) (32D G). 32D Epo1.1 is a revertant of 32D Epo and is capable of growing in IL-3. These cell lines express the differentiation program appropriate to the specific growth factor and depend on the growth factors not only for proliferation but also for survival. To determine how the signal for proliferation is triggered by various growth factors, we examined the DNA histograms and the expression of cell cycle-specific genes in the different cell lines. The cell cycle-specific genes analyzed were myc (early G1), myb (late G1), and the structural genes for the calcium- binding protein 2A9 (middle G1) and histone H3 (G1-S boundary). The DNA histogram analysis of cells in the logarithmic phase of growth showed that approximately 40% of 32D, 32D GM, 32D G, and 32D Epo1.1 (growing in IL-3) were cells with a 2N DNA content (and therefore in G0/G1), and another 40% have a DNA content intermediate between 2N and 4N (in S phase). In contrast, 32D Epo and 32D Epo1.1 (growing in Epo) had fewer cells in the G0/G1 phase of the cell cycle compared with the number of cells that were in the S phase (19% to 31% v 69% to 78%, respectively). Because all the cell lines have comparable doubling times (15 to 18 hours), the cell distribution among the phases of the cell cycle is proportional to the length of the phase. Therefore, cells growing in IL- 3 (32D and 32D Epo1.1), GM-CSF (32D GM), or G-CSF (32D G) progress along the cycle in a manner typical of previously reported nontransformed cell lines. In contrast, cells growing in Epo (32D Epo or 32D Epo1.1) spend relatively less time in G0/G1 and correspondingly more time in S. These data were confirmed by the analysis of the tritiated thymidine (3H-TdR) suicide rate and of the expression of cell cycle-specific genes. The 32D and 32D Epo1.1 cells growing in IL-3 had a suicide rate of congruent to 50%, whereas the suicide rate of 32D Epo and 32D Epo1.1 growing in Epo was higher than 75%.(ABSTRACT TRUNCATED AT 400 WORDS)