N-hydroxyacetaminophen: a postulated toxic metabolite of acetaminophen

The decomposition of N-hydroxyacetaminophen has been shown to occur via an initial first-order dehydration step to N-acetyl-p-benzoquinone imine with a rate constant at pH 7.6 of 8.66 x 10(-3) min-1 and a half-life of 80 min. This is followed by a complex reaction between the quinone imine and the N-hydroxy compound to ultimately yield p-nitrosophenol and acetaminophen. The glucuronide and sulfate conjugates of N-hydroxyacetaminophen have been observed as urinary metabolites of N-hydroxyacetaminophen. No N-hydroxylated metabolites were found among the metabolites of acetaminophen. These results have been interpreted to show that N-hydroxyacetaminophen is not a metabolite of acetaminophen. It is proposed that the hepatotoxicity and nephrotoxicity of acetaminophen are mediated by a direct oxidation of acetaminophen to the toxic reactive intermediate N-acetyl-p-benzoquinone imine by the cytochrome P450 dependent mixed-function oxidase system.     

The cost of antidepressant overdose

Ninety percent of suicide attempts referred to a general hospital are by self-poisoning. Among women, drug overdose is the commonest means of suicide. In a retrospective naturalistic review of 200 patients who were treated in the Critical Care Unit of a general hospital following medication overdose, 12% were antidepressant overdoses. The mean duration of hospital stay for overdose with tricyclic antidepressants (TCA) was more than double that for overdose with selective serotonin reuptake inhibitors (SSRI) (7 vs 3 days; z = 2.20, p < 0.05). The dollar cost of hospital treatment for patients who overdosed on TCAs was four times greater than that for patients who overdosed on SSRIs ($22,923 vs $5,379; z = 2.30, p < 0.05). The tricyclic compounds clearly have a price advantage over more recently introduced antidepressant agents fluoxetine, sertraline, paroxetine, venlafaxine, and bupropion. The apparent cost advantage of prescribing a less expensive drug may be nullified by the cost associated with adverse consequences.     

Characterization of a new lipopeptide surfactant produced by thermotolerant and halotolerant subsurface Bacillus licheniformis BAS50

Strain BAS50, isolated from a petroleum reservoir at a depth of 1,500 m and identified as Bacillus licheniformis, grew and produced a lipopeptide surfactant when cultured on a variety of substrates at salinities of up to 13% NaCl. Surfactant production occurred both aerobically and anaerobically and was optimal at 5% NaCl and temperatures between 35 and 45 degrees C. The biosurfactant, termed lichenysin A, was purified and chemically characterized. A tentative structure and composition for the surfactant are described. Lichenysin A is a mixture of lipopeptides, with the major components ranging in size from 1,006 to 1,034 Da. The lipid moiety contains a mixture of 14 linear and branched beta-hydroxy fatty acids ranging in size from C12 to C17. There are seven amino acids per molecule. The peptide moiety is composed of the following amino acids: glutamic acid as the N-terminal amino acid, asparagine, valine, leucine, and isoleucine as the C-terminal amino acid, at a ratio of 1.1:1.1:1.0:2.8:1.0, respectively. Purified lichenysin A decreases the surface tension of water from 72 mN/m to 28 mN/m and achieves the critical micelle concentration with as little as 12 mg/liter, characterizing the product as a powerful surface-active agent that compares favorably to others surfactants. The antibacterial activity of lichenysin A has been demonstrated.     

A new analogue scale for assessing children's pain: an initial validation study

A new instrument was designed to provide a practical clinical measure for assessing children's pain intensity and pain affect. The pocket size measure includes a Coloured Analogue Scale (CAS) to assess intensity and a facial affective scale to assess the aversive component of pain. Both scales have numerical ratings on the back, so that the person administering it can quickly note the numbers that represent a child's pain. This study was conducted to determine the validity of the new instrument by evaluating the psychophysical properties of the intensity scale and by evaluating the discriminant validity of the intensity and affective scales. Since visual analogue scales (VAS) are valid and reliable measures for assessing children's pain, children's ability to use the new analog scale was compared with their performance on a VAS. Children's ability to rate pain affect using an affective scale, in which the 9 faces on a Facial Affective Scale (FAS) are presented in an ordered sequence from least to most distressed, was compared to their performance on the original FAS, in which the same faces were presented in a random order. Using a parallel groups design, 104 children (5-16 years; 60 female, 44 male; 51 healthy and 53 with recurrent headaches) were randomized into two groups: CAS or VAS. Children used the assigned scale to complete a calibration task, in which they rated the sizes of 7 circles varying in area (491, 804, 1385, 2923, 3848, 5675 and 7854 mm2). The psychophysical function relating perceived circle size to actual physical size was determined for the CAS and VAS. Children's CAS and VAS responses on the calibration task yielded similar mathematical relationships: psi cas = 0.035I0.87, psi vas = 0.027I0.89, where psi = perceived magnitude and I = stimulus intensity. The R2 values were 0.921 and 0.922 for the CAS and VAS groups, respectively. Analyses of covariance revealed no significant differences in the characteristics of these relationships, i.e., R2, slope, or y intercept, by scale type. Children used the same scale to complete the Children's Pain Inventory (CPI), in which they rated the intensity and affect of 16 painful events (varying in nature and extent of tissue damage). Children's CAS and VAS responses on the CPI were similar. Analyses of covariance indicated that there were no differences in either intensity or affective ratings by scale type. However, the mean number of painful events experienced by children increased significantly with age (P = 0.0001). Intensity ratings decreased significantly with age (P = 0.002), but affective ratings did not vary with age. The new instrument has equivalent psychometric properties to a 165 mm VAS. However, the CAS was rated as easier to administer and score than the VAS, so it may be more practical for routine clinical use. Since the CAS has fulfilled the first two criteria for a pain measure (psychophysical properties and discriminant validity), it is ethical to proceed with the formal definitive test for construct validity, in which children from various clinical populations use the CAS scale to assess their own pain.     

Electrogenicity at the donor/acceptor sides of cyanobacterial photosystem I

To study electrogenesis the photosystem I particles from Synechococcus elongatus were incorporated into asolectin liposomes, and fast kinetics of laser flash-induced electric potential difference generation has been measured by a direct electrometric method in proteoliposomes absorbed on a phospholipid-impregnated collodion film. The photoelectric response has been found to involve three electrogenic stages associated with (i) iron-sulfur center Fx reduction by the primary electron donor P700, (ii) electron transfer between iron-sulfur centers Fx and FA/FB, and (iii) reduction of photo-oxidized P700+ by reduced cytochrome C553. The relative magnitudes of phases (ii) and (iii) comprised about 20% of phase (i).     

N-ras mutations in radiation-induced murine leukemic cells

N-ras mutations were examined in DNA samples extracted from the spleen of CBA/Ca mice that developed myeloid leukemia (ML) following exposure to radiations of different qualities. A total of 17 ML cases, i.e. 5 cases of neutron-induced and 12 cases of photon- (3 gamma-ray and 9 x-ray) induced ML were included in the study along with 12 DNA samples from the bone marrow cells of control mice. Polymerase chain reaction-single strand conformational polymorphisms (PCR-SSCP) and the direct sequencing of PCR products were used to analyze three regions of the N-ras gene: (i) a 120 base-pair (bp) long portion of exon I (codons 2-37); (ii) a 103 bp long portion of exon II (codons 48-82); and (iii) a 107 bp long portion of exon III (codons 118-150). PCR-SSCP mobility shifts indicated mutations within only exon II of the N-ras gene. Such mutations were more prevalent in samples from mice exposed to fast neutrons. The exact type and location of these mutations were then determined by direct DNA sequencing. Silent point mutations, i.e. base transitions at the third base of codons 57 (GAC-->GAT), 62 (CAA-->CAC), or 70 (CAG-->CAA) were present only in mice that developed ML after exposure to fast neutrons. A base transversion at the third base of codon 61 (CAA-->CAC) was also observed in some ML cases. DNA sequencing demonstrated that ML samples contained normal as well as mutated DNA sequences. The higher frequency of N-ras mutations in neutron-induced ML suggested that fast neutrons are more effective in inducing genomic instability at the N-ras region of the genome. More importantly, N-ras mutations are not the initiating event in radiation leukemogenesis. This conclusion was supported by the finding that N-ras mutations were detected only in mice with an overt leukemic phenotype but not in mice with minimal tissue infiltration of leukemic cells, suggesting that the disease may be present prior to the presence of N-ras mutations. Alternatively, N-ras may be present in these mice but a large number of normal spleen cells in these mice interferes with the detection of mutation in a small population of leukemic cells.