Screening for complement deficiency in bacterial meningitis

Seventy-seven children with bacterial meningitis were screened for complement deficiency. Both the classical and the alternate pathways were normal in 75 patients. Transiently reduced total haemolytic activity of the classical pathway was documented in a boy with meningococcal meningitis. Total haemolytic activity of both the classical and the alternate pathways were reduced in another patient with pneumococcal meningitis: individual complement components determination indicated predominant activation of the alternate pathway.     

Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats

Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR- based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1- responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.      

NFNA safety survey: a report of data collected in 1988 versus 1998

In 1998, the Air & Surface Transport Nurses Association ASTNA (formerly known as the National Flight Nurses Association [NFNA]) sponsored a follow-up safety survey to one it had conducted in 1988. The survey was sent out to all association members and identified whether a respondent of the survey was employed by a program that had policies addressing the safety topics identified in the survey and were compliant with the topic. Covered topics included scheduling practices, rest, refusal to fly because of safety issues, safety briefings, safety training, chemical restraints, hot off-loading, personal protective gear, and safety equipment installed in aircraft.

The 1998 NFNA safety survey replicated a safety survey sent in 1988. The results of the two surveys were compared using side-by-side analysis with graphic comparison of trends that have occurred during the 10-year period. With the exception of hot loading/unloading, every category of questions recognized an increased frequency of both written policies and compliance or practice. The most significant improvement in compliance was “personal protective gear;” the category engendering the most concern was “refusal to fly due to safety issues.” In 1998, only 52% of respondents worked in programs that “defined the flight nurses' responsibility and acceptable reasons for refusal to participate.”     

Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol).

PURPOSE: To compare the preclinical and clinical pharmacokinetic properties of paclitaxel formulated as a Cremophor-free, albumin-bound nanoparticle (ABI-007) and formulated in Cremophor-ethanol (Taxol). EXPERIMENTAL DESIGN: ABI-007 and Taxol were given i.v. to Harlan Sprague-Dawley male rats to determine pharmacokinetic and drug disposition. Paclitaxel pharmacokinetic properties also were assessed in 27 patients with advanced solid tumors who were randomly assigned to treatment with ABI-007 (260 mg/m(2), 30 minutes; n = 14) or Taxol (175 mg/m(2), 3 hours; n = 13), with cycles repeated every 3 weeks. RESULTS: The volume of distribution at steady state and clearance for paclitaxel formulated as Cremophor-free nanoparticle ABI-007 were significantly greater than those for paclitaxel formulated with Cremophor (Taxol) in rats. Fecal excretion was the main elimination pathway with both formulations. Consistent with the preclinical data, paclitaxel clearance and volume of distribution were significantly higher for ABI-007 than for Taxol in humans [21.13 versus 14.76 L/h/m(2) (P = 0.048) and 663.8 versus 433.4 L/m(2) (P = 0.040), respectively]. CONCLUSIONS: Paclitaxel formulated as ABI-007 differs from paclitaxel formulated as Taxol, with a higher plasma clearance and a larger volume of distribution. This finding is consistent with the absence of paclitaxel-sequestering Cremophor micelles after administration of ABI-007. This unique property of ABI-007 could be important for its therapeutic effectiveness.     

Phase II trial of oral aminopterin for adults and children with refractory acute leukemia.

PURPOSE: To determine the antileukemic activity of weekly oral aminopterin in patients with refractory acute leukemia; to describe the pharmacodynamic properties of aminopterin; and to contrast the intracellular metabolism of aminopterin and methotrexate by patients' blasts in vitro. EXPERIMENTAL DESIGN: Forty-six patients were enrolled in three strata: children with acute lymphoblastic leukemia (ALL), adults with ALL, and patients with acute myeloid leukemia (AML). Aminopterin was given weekly, in two doses of 2 mg/m(2), 12 hours apart. Limited sampling pharmacokinetic analysis was done during the first week of therapy. Accumulation of [(3)H]aminopterin and [(3)H]methotrexate by leukemic blasts was studied in vitro. RESULTS: Six of 22 children with ALL (27%; 95% confidence interval, 8-47%) had clinically significant responses. None of those with AML and only two of 11 adults with ALL had responses meeting protocol definitions, although peripheral blast counts tended to decrease with therapy in all groups. Mucosal toxicity was minimal, even with limited use of leucovorin rescue. Complete bioavailability of aminopterin was confirmed, with a mean area under the curve of 0.52 +/- 0.03 micromol hour/L after oral dosing. No relationship between aminopterin pharmacokinetics and response was seen. In vitro, aminopterin showed more consistent metabolism by leukemic blasts to polyglutamates than methotrexate. Lineage-specific differences in the pattern of intracellular antifolylpolyglutamates were observed. CONCLUSIONS: Weekly oral aminopterin has significant activity among children with refractory ALL. With greater cellular accumulation and metabolism, more reliable bioavailability than methotrexate, and tolerable toxicity at this dose and schedule, aminopterin deserves further study as a potent alternative to methotrexate.