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PubMed2001

Implementation and pharmacoeconomic analysis of a clinical staff pharmacist practice model.

The implementation and pharmacoeconomic analysis of a clinical staff pharmacist (CSP) practice model are described. Staff pharmacists at a large, tertiary care, academic medical center were selected and trained to perform clinical pharmacy services under the direction of clinical pharmacy specialist mentors. Clinical interventions by these CSP practitioners were evaluated in terms of direct cost savings (the difference in actual acquisition costs between therapies) and cost avoidance (the dollar value of adverse drug events [ADEs] avoided). The CSPs performed a total of 4959 interventions during a 12-month period. The interventions provided direct cost savings of $92,076 and an estimated cost avoidance of $488,436. Comparing cost savings and cost avoidance with the expenses of providing these services indicated a net economic benefit of $392,660. A new model of pharmacy practice that integrates staff pharmacists into existing clinical practice has the potential to minimize the risks, decrease the costs, and improve the outcomes associated with drug therapy.

Cost Savings↗

PubMed2003

Nature of preventable adverse drug events in hospitals: a literature review.

A literature review was conducted to identify the drug classes, types of errors, and types of adverse outcomes related to preventable adverse drug events (pADEs). Studies were identified by keyword search of MEDLINE and International Pharmaceutical Abstracts and by a manual search. The search was limited to peer-reviewed literature reporting pADEs in hospitalized patients and the frequencies of at least one pADE characteristic. The frequencies of pADEs and their characteristics were summarized using median and range. Ten studies published between 1994 and 2001 were included in the review. The reported median frequency of pADEs was 1.8% (range, 1.3-7.8%), and the median preventability rate of ADEs in the hospitals was 35.2% (range, 18.7-73.2%). Cardiovascular drugs were implicated for 17.9% of pADEs (range, 4.3-28.1%). Most pADEs occurred in the prescribing stage of the medication-use process and were dose related. Inappropriate prescribing decisions and patient monitoring were the most frequently identified causes of pADEs. The most common adverse outcomes were allergic reactions, hepatic or renal problems, cardiovascular problems, hematologic problems and bleeding, and central nervous system problems. Frequently reported examples of pADEs included antihypertensive overdose associated with bradycardia or hypotension, antiinfectives prescribed despite a history of allergy, warfarin overdose and inappropriate monitoring resulting in hemorrhage, and opioid overdose or underdose associated with respiratory depression or poor pain control, respectively. Despite the heterogeneity of pADEs, the results of this literature review suggest that a few types of drugs, errors, and adverse outcomes constitute a substantial proportion of pADEs. Targeting these high-priority areas could significantly reduce the overall frequency of pADEs.

Adverse Drug Reaction Reporting Systems↗

PubMedDate not supplied

Chronic footshock, but not a physiological stressor, suppresses the alcohol deprivation effect in dependent rats.

AIMS: Unlike in humans, the link between chronic stress and increased alcohol consumption in laboratory animals is equivocal. Two factors may contribute to this: a lack of studies examining the effects of stress on consumption in dependent rats and differences in the nature of the stressor. Moreover, to our knowledge, the effects of different types of stress on the alcohol deprivation effect (ADE), the temporary increase in alcohol consumption seen after periods of abstinence, has not been previously examined. METHODS: In the present study, dependent rats previously trained to self-administer alcohol, received either no stress, chronic daily intermittent footshock (10 min/day for 7 days) or daily (for 7 days) injections of lipopolysaccharide, a physiological stressor. Alcohol-reinforced responding was then measured for 20 days. RESULTS: Only control animals and those treated with LPS exhibited an alcohol deprivation effect and increased consumption. CONCLUSIONS: Taken together, these data suggest that chronic footshock may not be an appropriate paradigm to study the impact of stress on alcohol consumption.

Alcoholism↗

PubMed1997

Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene.

The carcinogenicity of estrogens in rodents and man has been attributed to either alkylation of cellular macromolecules and/or redox-cycling, generation of active radicals and DNA damage. Metabolic activation of estradiol leading to the formation of catechol estrogens is believed to be a prerequisite for its genotoxic effects. 4-Hydroxyestradiol is a potent inducer of tumors in hamsters. Previous studies have shown that 3,4-estrone quinone (3,4-EQ) can redox-cycle and is capable of inducing exclusively single strand DNA breaks in MCF-7 breast cancer cells, as well as react with various nucleophiles including amino acids and nucleic acids to give Michael addition products. In this paper we examined the nature of the interaction of 3,4-EQ with COIII gene and analysed the estrogen-DNA adducts by 32P-post-labeling. The reaction of 3,4-EQ with the COIII gene followed by polymerase arrest assay showed several stop sites in which guanine was preferentially attacked by 3,4-EQ and, to a lesser extent, with Ade, Cyt and Thy. 32P-Post-labeling analysis of the reaction of 3,4-EQ with COIII gene gave one major adduct which was found to be identical to that obtained from reaction of dGMP with 3,4-EQ. The observation that obstruction of in vitro replication of COIII template bound to 3,4-EQ suggests that estrogen quinone adducted lesions can arrest DNA polymerase. These results indicate that 3,4-EQ may be genotoxic and may provide one possible explanation for the carcinogenic effects of estrogens.

Binding Sites↗

PubMed1982

The induction of SCE and chromosomal aberrations with relation to specific base methylation of DNA in Chinese hamster cells by N-methyl-N-nitrosourea and dimethyl sulphate.

Chinese hamster cells (V79) were treated, either as exponentially proliferating cultures or under conditions where they were density-inhibited, with various doses of the potent carcinogen N-methyl-N-nitrosourea (MNU) or the relatively weak carcinogen dimethylsulphate (DMS). The colony forming ability of these cells and the induced frequencies of sister chromatid exchanges (SCEs) and chromosomal aberrations were assayed. Following the exposure of density-inhibited cells to radio-labelled methylating agents (labelled in the methyl group) these phenomena were related to the levels of 7-methylguanine (7-meGua), O6-methylguanine (O6-meGua) and 3-methyladenine (3-me-Ade) in the DNA. At equitoxic doses MNU and DMS induced similar frequencies of SCEs and chromosomal aberrations. Since, at equitoxic doses, MNU produces approximately 20 times more O6-meGua in V79 cell DNA than does DMS, this indicates that the formation of O6-meGua in DNA is not a major cause of SCEs and chromosomal aberrations. DMS-induced SCEs may be mediated via the production of both 3-meAde and 7-meGua in the DNA; these two methylated purines may also be responsible for MNU-induced SCEs. Therefore, no one specific methylated purine was identified as being solely accountable for the formation of SCEs. Also, the repair of lesions in the DNA of non-replicating V79 cells leads to a reduction in the SCE frequency on their subsequent release from the density-inhibited state, suggesting that repair is not intimately responsible for their formation. No association was discernable between chromosomal aberrations and any of the three methylated purines studied.

Animals↗

PubMed2003

Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo.

Studies of estrogen metabolism, formation of DNA adducts, carcinogenicity, cell transformation and mutagenicity have led to the hypothesis that reaction of certain estrogen metabolites, predominantly catechol estrogen-3,4-quinones, with DNA can generate the critical mutations initiating breast, prostate and other cancers. The endogenous estrogens estrone (E1) and estradiol (E2) are oxidized to catechol estrogens (CE), 2- and 4-hydroxylated estrogens, which can be further oxidized to CE quinones. To determine possible DNA adducts of E1(E2)-3,4-quinones [E1(E2)-3,4-Q], we reported previously that the reaction of E1(E2)-3,4-Q with dG produces the depurinating adduct 4-hydroxyE1(E2)-1-N7Gua [4-OHE1(E2)-1-N7Gua] by 1,4-Michael addition (Stack et al., Chem. Res. Toxicol., 1996, 9, 851). We report here that reaction of E1(E2)-3,4-Q with Ade results in the formation of 4-OHE1(E2)-1-N3Ade by 1,4-Michael addition. The N7Gua and N3Ade depurinating adducts formed both in vitro and in rat mammary gland in vivo were analyzed by HPLC with electrochemical detection and, for some samples, by LC/MS/MS. When E2-3,4-Q was reacted with DNA in vitro, the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua, which are rapidly lost from DNA by cleavage of the glycosyl bond, were formed (>99% of the total adducts), as well as traces of stable adducts, which remain in DNA unless removed by repair. Similar results were obtained when 4-OHE2 was oxidized by horseradish peroxidase, lactoperoxidase, tyrosinase or phenobarbital-induced rat liver microsomes in the presence of DNA. When 4-OHE2 or E2-3,4-Q was injected into the mammary glands of female ACI rats in vivo and the mammary tissue was excised 1 h later, the depurinating adducts 4-OHE2-1-N3Ade and 4-OHE2-1-N7Gua constituted >99% of the total adducts formed. In addition, 4-OHE2 conjugates formed by reaction of E2-3,4-Q with glutathione were also detected. These results demonstrate that the 4-CE are metabolized to CE-3,4-Q, which react with DNA to form primarily depurinating adducts. These adducts can generate the critical mutations that initiate cancer (Chakravarti et al., Oncogene, 2001, 20, 7945; Chakravarti et al., Proc. Am. Assoc. Cancer Res., 2003, 44, 180).

Animals↗

PubMed1989

Molecular characterization of the Aspergillus nidulans yA locus.

We investigated the molecular organization of the region of Aspergillus nidulans chromosome I containing yA, a gene encoding the developmentally regulated enzyme conidial laccase. DNA fragments were identified that complemented the yA2 mutation and were shown to correspond to yA by genetic mapping and gene disruption experiments. The molecular map of the region was oriented to the genetic map by testing DNA fragments for their ability to complement a mutation in the tightly linked adE gene. The yA gene codes for a 2200 nucleotide mRNA that is present at low levels in vegetative cells and mature conidia, but accumulates to high levels in sporulating cultures. yA mRNA appears shortly after differentiation of sporogenous phialide cells. It accumulates in two developmentally abnormal mutant strains that produce phialides but is absent from two mutant strains that do not produce phialides. Thus, yA transcription is probably restricted to phialides. This result is discussed in relationship to the physiological roles played by phialides in spore differentiation.

Aspergillus nidulans↗

PubMed1991

Isolation and characterization of Schizosaccharomyces pombe mutants affected in mitotic recombination.

A haploid Schizosaccharomyces pombe strain carrying a heteroallelic duplication of the ade6 gene was used to isolate mitotic recombination-deficient mutants. Recombination between the different copies of the ade6 gene can lead to Ade+ segregants. These are observed as growing papillae when colonies of a suitable size are replicated onto selective medium. We isolated mutants which show an altered papillation phenotype. With two exceptions, they exhibit a decrease in the frequency of mitotic recombination between the heteroalleles of the duplication. The two other mutants display a hyper-recombination phenotype. The 12 mutations were allocated to at least nine distinct loci by recombination tests. Of the eight rec mutants analyzed further, six were also affected in mitotic intergenic recombination in the intervals cen2-mat or cen3-arg 1. No effect on mitotic intragenic recombination was observed. These data suggest that mitotic gene conversion and crossing over can be separated mutationally. Meiotic recombination occurs at the wild-type frequency in all mutants investigated.

Adenine↗

PubMed1992

Effects of mutagen-sensitive mus mutations on spontaneous mitotic recombination in Aspergillus.

Methyl methane-sulfonate (MMS)-sensitive, radiation-induced mutants of Aspergillus were shown to define nine new DNA repair genes, musK to musS. To test mus mutations for effects on mitotic recombination, intergenic crossing over was assayed between color markers and their centromeres, and intragenic recombination between two distinguishable adE alleles. Of eight mutants analyzed, four showed significant deviations from mus+ controls in both tests. Two mutations, musK and musL, reduced recombination, while musN and musQ caused increases. In contrast, musO diploids produced significantly higher levels only for intragenic recombination. Effects were relatively small, but averages between hypo- and hyperrec mus differed 15-20-fold. In musL diploids, most of the rare color segregants resulted from mitotic malsegregation rather than intergenic crossing over. This indicates that the musL gene product is required for recombination and that DNA lesions lead to chromosome loss when it is deficient. In addition, analysis of the genotypes of intragenic (ad+) recombinants showed that the musL mutation specifically reduced single allele conversion but increased complex conversion types (especially recombinants homozygous for ad+). Similar analysis revealed differences between the effects of two hyperrec mutations; musN apparently caused high levels solely of mitotic crossing over, while musQ increased various conversion types but not reciprocal crossovers. These results suggest that mitotic gene conversion and crossing over, while generally associated, are affected differentially in some of the mus strains of Aspergillus nidulans.

Aspergillus nidulans↗

PubMed1998

The yeast HSM3 gene acts in one of the mismatch repair pathways.

Mutants with enhanced spontaneous mutability (hsm) to canavanine resistance were induced by N-methyl-N-nitrosourea in Saccharomyces cerevisiae. One bearing the hsm3-1 mutation was used for this study. This mutation does not increase sensitivity to the lethal action of different mutagens. The hsm3-1 mutation produces a mutator phenotype, enhancing the rates of spontaneous mutation to canavanine resistance and reversions of lys1-1 and his1-7. This mutation increases the rate of intragenic mitotic recombination at the ADE2 gene. The ability of the hsm3 mutant to correct DNA heteroduplex is reduced in comparison with the wild-type strain. All these phenotypes are similar to ones caused by pms1, mlhl and msh2 mutations. In contrast to these mutations, hsm3-1 increases the frequency of ade mutations induced by 6-HAP and UV light. Epistasis analysis of double mutants shows that the PMS1 and HSM3 genes control different mismatch repair systems. The HSM3 gene maps to the right arm of chromosome II, 25 cM distal to the HIS7 gene. Strains that bear a deleted open reading frame YBR272c have the genetic properties of the hsm3 mutant. The HSM3 product shows weak similarity to predicted products of the yeast MSH genes (homologs of the Escherichia coli mutS gene). The HSM3 gene may be a member of the yeast MutS homolog family, but its function in DNA metabolism differs from the functions of other yeast MutS homologs.

Amino Acid Sequence↗

PubMed2000

The product of the DNA damage-inducible gene of Saccharomyces cerevisiae, DIN7, specifically functions in mitochondria.

We reported previously that the product of the DNA damage-inducible gene of Saccharomyces cerevisiae, DIN7, belongs to a family of proteins that are involved in DNA repair and replication. The family includes S. cerevisiae proteins Rad2p and its human homolog XPGC, Rad27p and its mammalian homolog FEN-1, and Exonuclease I (Exo I). Here, we report that Din7p specifically affects metabolism of mitochondrial DNA (mtDNA). We have found that dun1 strains, defective in the transcriptional activation of the DNA damage-inducible genes RNR1, RNR2, and RNR3, exhibit an increased frequency in the formation of the mitochondrial petite (rho(-)) mutants. This high frequency of petites arising in the dun1 strains is significantly reduced by the din7::URA3 allele. On the other hand, overproduction of Din7p from the DIN7 gene placed under control of the GAL1 promoter dramatically increases the frequency of petite formation and the frequency of mitochondrial mutations conferring resistance to erythromycin (E(r)). The frequencies of chromosomal mutations conferring resistance to canavanine (Can(r)) or adenine prototrophy (Ade(+)) are not affected by enhanced synthesis of Din7p. Experiments using Din7p fused to the green fluorescent protein (GFP) and cell fractionation experiments indicate that the protein is located in mitochondria. A possible mechanism that may be responsible for the decreased stability of the mitochondrial genome in S. cerevisiae cells with elevated levels of Din7p is discussed.

Base Sequence↗

PubMed1979

Potentiation of experimental allergic encephalomyelitis in hamsters with persistent encephalitis due to measles virus.

To clarify mechanisms underlying acute disseminated encephalomyelitis (ADE) in patients with infection due to measles or other viruses, a new animal model was devised. Adult hamsters that had clinically recovered from acute encephalitis induced by prior intracerebral injection of the HBS strain of measles virus were challenged with neuroantigen plus adjuvant. Such hamsters, which had a high likelihood of carrying persistent HBS measles virus in the central nervous system (CNS), exhibited a significantly higher incidence of experimental allergic encephalomyelitis (EAE) following challenge as compared with simultaneously challenged but previously uninfected littermates. Occurrence of EAE in hamsters previously injected with heat-inactivated virus was not potentiated, a finding suggesting that persistence of the virus in the CNS renders that organ system more vulnerable to immunologic attack. This new model has promise for the probing of relationships between persistent viral infections of the CNS and host autoimmune responses directed against that target organ system.

Acute Disease↗

PubMed2000

Rapid effects of nitrogen form on leaf morphogenesis in tobacco.

Ammonium (NH4+) instead of nitrate (NO3-) as the nitrogen (N) source for tobacco (Nicotiana tabacum L.) cultivated in a pH-buffered nutrient solution resulted in decreased shoot and root biomass. Reduction of shoot fresh weight was mainly related to inhibition of leaf growth, which was already detectable after short-term NH4+ treatments of 24 h, and even at a moderate concentration level of 2 mM. Microscopic analysis of the epidermis of fully expanded leaves revealed a decrease in cell number (50%) and in cell size (30%) indicating that both cell division and cell elongation were affected by NH4+ application. Changes in various physiological parameters known to be associated with NH4(+)-induced growth depression were examined both in long-term and short-term experiments: the concentrations of total N, soluble sugars and starch as well as the osmotic potential, the apparent hydraulic conductivity and the rate of water uptake were not reduced by NH4+ treatments (duration 1-12 d), suggesting that leaf growth was neither limited by the availability of N and carbohydrates, nor by a lack of osmotica or water supply. Although the concentration of K+ in leaf press sap declined in expanding leaves by approximately 15% in response to NH4+ nutrition, limitation of mineral nutrients seems to be unlikely in view of the fast response of leaf growth at 24 h after the start of the NH4+ treatment. No inhibitory effects were observed when NH4+ and NO3- were applied simultaneously (each 1 mM) resulting in a NO3-/NH4+ net uptake ratio of 6:4. These findings suggest that the rapid inhibition of leaf growth was not primarily related to NH4+ toxicity, but to the lack of NO3(-)-supply. Growth inhibition of plants fed solely with NH4+ was associated with a 60% reduction of the zeatine + zeatine riboside (Z + ZR) cytokinin fraction in the xylem sap after 24 h. Furthermore Z + ZR levels declined to almost zero within the next 4 d after start of the NH4+ treatment. In contrast, the concentrations of the putative Z + ZR precursors isopentenyl-adenine and isopentenyl-adenosine (i-Ade + i-Ado) were not affected by NH4+ application. Since cytokinins are involved in the regulation of both cell division and cell elongation, it seems likely that the presence of NO3- is required to maintain biosynthesis and/or root to shoot transfer of cytokinins at a level that is sufficient to mediate normal leaf morphogenesis.

Carbohydrate Metabolism↗

PubMed1986

Genetic effects of methylmethanesulphonate during meiosis in Saccharomyces cerevisiae.

Enhanced mutagenic action after methylmethanesulphonate (MMS) treatment was found in pre-replicative meiotic yeast cells of the strain D7. The level of gene conversion after MMS treatment rose above the spontaneous level during the period of commitment to meiotic recombination, but at later times into meiosis became indistinguishable from the full meiotic level. In contrast reciprocal recombination detected between ade 2 and the centromere of chromosome XV after MMS treatment remained above the spontaneous level up to commitment to meiotic cell division with relatively high levels through meiotic prophase I. These results are discussed in relation to MMS-induced damage and its repair, particularly double-strand break repair.

Gene Conversion↗

PubMed1990

Chemical synthesis of biologically active oligoribonucleotides using beta-cyanoethyl protected ribonucleoside phosphoramidites.

The preparation of fully protected diisopropylamino-beta-cyanoethyl ribonucleoside phosphoramidites with regioisomeric purity greater than 99.95% is described. It is demonstrated that the combination of standard DNA protecting groups, 5'-O-DMT, N-Bz (Ade and Cyt), N-iBu (Gua), beta-cyanoethyl for phosphate, in conjunction with TBDMS for 2'-hydroxyl protection, constitutes a reliable method for the preparation of fully active RNA. Average stepwise coupling yields in excess of 99% were achieved with these synthons on standard DNA synthesizers. Two steps completely deprotect the oligoribonucleotide and workup is reduced to a fifteen minute procedure. Further, it is shown that the deprotected oligoribonucleotides are free from 5'-2' linkages. This methodology was applied to the chemical synthesis of a 24-mer microhelix, a 35-mer minihelix and two halves of a catalytic 'Hammerhead Ribozyme'. These oligoribonucleotides were directly compared in two distinct biochemical assays with enzymatically (T7 RNA polymerase) prepared oligoribonucleotides and shown to possess equal or better activity.

Base Sequence↗

PubMed1991

Effects of 2-chloroadenine substitution in DNA on restriction endonuclease cleavage reactions.

The purine analog, 2-chloro-2'-deoxyadenosine triphosphate (CldATP), was incorporated enzymatically in place of dATP into the minus strand of M13mp18 duplex DNA. Its effect on protein-DNA interactions was assessed by determining the amount of DNA cleavage by type II restriction endonucleases. Substitution of chloroadenine (CIAde) for adenine (Ade) in DNA appreciably decreased the amount and rate of DNA cleavage of the minus strand when the analog was situated within the appropriate endonuclease recognition site. CIAde residues flanking a restriction site had variable effects. SmaI cleaved both CIAde-containing and control substrates with equal efficiency. NarI, however, was stimulated 1.5-fold by the presence of CIAde outside its recognition site. The effects of analog incorporation on restriction enzyme cleavage of an opposing unsubstituted strand of duplex DNA was examined by enzymatically incorporating CIdATP into the complementary minus strand of a 36-base oligonucleotide. Endonucleolytic cleavage of both plus and minus strands was reduced on 36-mers containing CIAde residues located within only the minus strand. These data suggest that CIAde residues incorporated into a single DNA strand may have an appreciable effect on DNA-protein interactions that involve one or both strands of duplex DNA.

Adenine↗

PubMed1991

A directed DNA sequencing strategy based upon Tn3 transposon mutagenesis: application to the ADE1 locus on Saccharomyces cerevisiae chromosome I.

We have developed a directed DNA sequencing strategy based upon the Escherichia coli transposon Tn3. This transposon displays little sequence specificity for transposition and is thus well suited to this task. Both mini-Tn3 transposons and sequencing vectors bearing the phage f1 single stranded origin of replication have been constructed. Upon mutagenesis of a target sequence, a population is produced in which each clone has two f1 origins of replication, one of which is at a variable position depending upon the transposon insertion site. When helper phage is added to the mutagenised population, the two f1 origins present on each clone are nicked, dividing the packaged strand into two segments, each of which is packaged into a separate phage particle. One of these segments contains no resistance markers and is lost, whilst the other is recovered as a deleted clone with a single chimeric f1 origin. A unidirectionally, variably-deleted set of sequencing clones is produced, and appropriately sized clones are sequenced using a primer complimentary to the transposon end. In addition to being inexpensive, the method does not require the same degree of technical expertise needed for many in vitro, enzymatically based methods. The strategy has been used to determine 2.6 kilobases of nucleotide sequence in the Saccharomyces cerevisiae ADE 1 locus.

Amino Acid Sequence↗

PubMed1975

tRNA tertiary structure in solution as probed by the photochemically induced 8-13 cross-link.

The conformation of ten purified tRNAs from Escherichia Coli has been investigated by means of the photo-induced cross-linking of 4Srd8 and Cyd13, which is sensitive to the juxtaposition of the two bases. Three tRNAs photo-react abnormally slowly; tRNAPhe, tRNAMet/m a and tRNAVal/2; a comparison with normally reacting species suggests that base 47 (Urd or modified Urd) is involved in a tertiary interaction in Class I tRNAs with the triplet 8, 14, 28. The UGA suppressor tRNATrp photoreacts significantly slower than the wild type. Thus the single base change Gua 24 to Ade induces a conformational change that alters the rate constant for the cross-linking reaction.

Base Sequence↗