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PubMed2006

Clinical features and correlates of gemcitabine-associated lung injury: findings from the RADAR project.

BACKGROUND: Gemcitabine is a commonly used chemotherapeutic agent structurally and pharmacologically similar to cytarabine. Recently, instances of severe gemcitabine-associated lung injury have been reported. Herein, investigators affiliated with the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program evaluated clinical characteristics of gemcitabine-associated severe acute lung injury from clinical trial reports, medical literature case reports, and spontaneous reports to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). METHODS: Clinical data were obtained by reviewing adverse event case reports for gemcitabine-associated lung injury as reported in the medical literature and in the FDA AERS database. Upper limit estimates of ADE rate were derived from review of published clinical trials reporting gemcitabine-associated lung injury rates of 10% or higher. RESULTS: A total of 178 reports of gencitabine-associated lung injury were identified; in AERS, there were 55 cases from clinical trials and 92 spontaneous reports. A comprehensive search revealed 31 medical literature reports. Clinical features of gemcitabine-associated lung injury included dyspnea, fever, pulmonary infiltrate, and cough with recognition of toxicity occurring after a median duration of 48 (range, 1-529) days after initiation of gemcitabine. The taxanes, docetaxel and paclitaxel, were frequently reported as coadministered therapies. Eleven Phase II or Phase III clinical trials with 317 patients identified gemcitabine-associated lung injury rates of greater than 10%, with the highest rates (22% and 42%) being observed in Phase III clinical trials where Hodgkin disease patients were treated with a regimen that included gemcitabine and bleomycin. CONCLUSIONS: High rates of gemcitabine-associated severe lung injury were observed when gemcitabine was combined with other therapies known to also cause lung injury. Physicians should have a high index of suspicion for this toxicity and report the relevant clinical findings to the FDA's AERS.

Antimetabolites, Antineoplastic↗

PubMed2005

Complementary and alternative therapies for cerebral palsy.

The optimal practice of medicine includes integrating individual clinical expertise with the best available clinical evidence from systematic research. This article reviews nine treatment modalities used for children who have cerebral palsy (CP), including hyperbaric oxygen, the Adeli Suit, patterning, electrical stimulation, conductive education, equine-assisted therapy, craniosacral therapy, Feldenkrais therapy, and acupuncture. Unfortunately, these modalities have different degrees of published evidence to support or refute their effectiveness. Uncontrolled and controlled trials of hippotherapy have shown beneficial effects on body structures and functioning. Studies of acupuncture are promising, but more studies are required before specific recommendations can be made. Most studies of patterning have been negative and its use cannot be recommended. However, for the other interventions, such as hyperbaric oxygen, more evidence is required before recommendations can be made. The individual with CP and his or her family have a right to full disclosure of all possible treatment options and whatever knowledge currently is available regarding these therapies.

Acupuncture Therapy↗

PubMed2005

Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions.

PURPOSE: To assess the frequency of potential azole-drug interactions and consequences of interactions between fluconazole and other drugs in routine inpatient care. METHODS: We performed a retrospective cohort study of hospitalized patients treated for systemic fungal infections with an oral or intravenous azole medication between July 1997 and June 2001 in a tertiary care hospital. We recorded the concomitant use of medications known to interact with azole antifungals and measured the frequency of potential azole drug interactions, which we considered to be present when both drugs were given together. We then performed a chart review on a random sample of admissions in which patients were exposed to a potential moderate or major drug interaction with fluconazole. The list of azole-interacting medications and the severity of interaction were derived from the DRUGDEX System and Drug Interaction Facts. RESULTS: Among the 4,185 admissions in which azole agents (fluconazole, itraconazole or ketoconazole) were given, 2,941 (70.3%) admissions experienced potential azole-drug interactions, which included 2,716 (92.3%) admissions experiencing potential fluconazole interactions. The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3%), midazolam (17.5%), warfarin (14.7%), methylprednisolone (14.1%), cyclosporine (10.7%) and nifedipine (10.1%). Charts were reviewed for 199 admissions in which patients were exposed to potential fluconazole drug interactions. While four adverse drug events (ADEs) caused by fluconazole were found, none was felt to be caused by a drug-drug interaction (DDI), although in one instance fluconazole may have contributed. CONCLUSIONS: Potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.

Adverse Drug Reaction Reporting Systems↗

PubMed2007

Outpatient drug safety: new steps in an old direction.

Iatrogenic injury from adverse drug events (ADEs) is a common and often preventable problem in modern medical practice. Attention to this problem has focused on the inpatient hospital setting and healthcare professionals. However, most medication is prescribed and used outside of hospitals and is managed by patients or lay caregivers in homes or workplaces. To address the public health problem of outpatient drug safety, interventions to prevent adverse events must recognize the central role of the patient in medication management and environmental factors specific to the outpatient setting. Lessons and techniques from the field of injury prevention should guide the development and implementation of safety interventions. First, Haddon's phase-factor matrix can be used to help conceptualize outpatient drug safety interventions. Second, interventions to improve outpatient drug safety should be patient-centered and extend beyond patient education to include engineering innovations and enforcement strategies. Third, the sustainability of active versus passive interventions should be considered when choosing safety interventions.

Ambulatory Care↗

PubMed2007

Estimating incidence of HIV infection in childbearing age African women using serial prevalence data from antenatal clinics.

Ades and Medley provided the first flexible method for estimating age- and time-specific HIV incidence using HIV prevalence data collected among pregnant women and adjusting for the effect of differential selection between infected and uninfected women. This paper extends the approach proposed by these authors. We used a parametric model that allows the relative inclusion rate to depend on both age, calendar time, and duration of HIV infection. We developed a two dimensional penalized log-likelihood approach for estimating time- and age-specific incidence using a binomial likelihood function and a quadratic roughness penalty which allows smoothing over both age and time. Identifiability of the model parameters and effect of sample size are studied through simulations. The method is illustrated using prenatal HIV testing data recorded from 1995 to 2002 in Abidjan, Côte d'Ivoire, to estimate the HIV annual incidence rate among women aged 12-40 year old, from the beginning of the epidemic to 2002. We show that estimated incidence rates are highly dependent on hypotheses made to model the relative inclusion rate. Despite this dependency, the application of the method leads to new and accurate findings on HIV incidence qualitative features in Abidjan. We highlight the relevance of such a method in monitoring the dynamics of HIV epidemic in Africa which is essential for planning vaccine trials and future treatment needs, and for assessment of prevention policy.

Adolescent↗

PubMed1984

Genetic effects of procarbazine in the yeast Saccharomyces cerevisiae, strain D4.

Procarbazine ( PCZ ) was tested for its ability to induce mitotic gene conversions at the ade and trp loci of Saccharomyces cerevisiae, strain D4. The influence of the following factors was examined: growth phase of the yeast cells (log vs stationary phase), pH of the treatment solution, and addition of mouse S9 fractions prepared from different organs. The drug was found more toxic and mutagenic at low doses (up to 25 mg/ml) for log phase cells, and scarcely toxic but highly mutagenic, even at high doses, for stationary phase cells. PCZ activity was reduced by acidic pH, and suppressed by S9 mix. Gene conversions were also analyzed in the intrasanguineous host-mediated assay performed in mice orally administered with PCZ . In such conditions PCZ was ineffective in stimulating mitotic gene conversions, probably owing to its inactivation in the acidic environment of the gastroenteric tract.

Animals↗

PubMed1984

Comparative genetic activity of cis- and trans-1,2-dichloroethylene in yeast.

The cis and trans isomers of 1,2-dichloroethylene were tested for mutagenic effects in a diploid strain (D7) of the yeast Saccharomyces cerevisiae in suspension tests with and without a mammalian microsomal activation system, an S9 mouse liver fraction, and by an in vivo intrasanguineous host mediated assay. The effects of the same agents on aminopyrine N-demethylase activity and cytochrome P-450 level in liver were studied in nonpretreated and in phenobarbital + beta-naphtoflavone-pretreated mice. In the suspension test, both isomers exhibited dose dependent toxicity, and survival was lower with metabolic activation than without. In this test also, both isomers exhibited genetic activity as measured by increases in recombinants at the ade 2 locus in experiments with metabolic activation. In the host-mediated assay, only the cis isomer showed evidence of mutagenic activity with significant increases in convertants at the trp locus and revertants at the ilv locus. Such mutagenic activity was found both after acute and chronic doses and in liver, kidney, and lung tissue. The two isomers exhibited different effects with respect to aminopyrine N-demethylase activity and cytochrome P-450 level. In general, the trans isomer appeared to emphasize induction of enzyme activity or level while the cis isomer more frequently tended to inhibit activity or destroy the enzyme.

Aminopyrine N-Demethylase↗

PubMed1987

Molecular cloning of chromosome I DNA from Saccharomyces cerevisiae: isolation of the MAK16 gene and analysis of an adjacent gene essential for growth at low temperatures.

MAK16 is an essential gene on chromosome I defined by the thermosensitive lethal mak16-1 mutation. MAK16 is also necessary for M double-stranded RNA replication at the permissive temperature for cell growth. As part of an effort to clone all the DNA from chromosome I, plasmids that complemented both the temperature-sensitive growth defect, and the M1 replication defects of mak16-1 strains were isolated from a plasmid YCp50: Saccharomyces cerevisiae recombinant DNA library. The two plasmids analysed contained overlapping inserts that hybridized proportionally to strains carrying different dosages of chromosome I. Furthermore, integration of a fragment of one of these clones occurred at a site linked to ade 1, confirming that this clone was derived from the appropriate region of chromosome I. An open reading frame adjacent to MAK16 potentially coding for a 468 amino acid protein was defined by sequence analysis. 185 amino acids of this open reading frame were replaced with a 1.2 kb fragment carrying the S. cerevisiae URA3 gene by a one-step gene disruption. The resulting strains grew at a rate indistinguishable from the wild type at 20 degrees C, 30 degrees C, or 37 degrees C, but could not grow at 8 degrees C. The deleted region is thus essential only at 8 degrees C, and we name this gene LTE1 (low temperature essential).

Base Sequence↗

PubMed1991

On the dependence of spontaneous mutation rates on the functional state of genes.

Spontaneous mutation of some genes was studied in haploid adenine and leucine auxotrophic yeast Saccharomyces. It was shown that a decrease in the amount of adenine (from 500 to 0 mg l-1) or leucine (from 300 to 0.3 mg l-1) in the medium, simultaneously with the transition from repression to derepression of the biosynthesis of these metabolites, resulted in a 15- to 150-fold increase in the reversion rate of genes ade 2 and leu2, respectively, for different strains. At the same time the mutation rate of suppressor genes varied relatively little (up to five-fold), and that of gene lys did not change at all. It was also demonstrated (on gene leu2) that the mutation rate is determined by the composition of the nutrient medium at the time of the S-phase of the cell cycle and it does not depend on the cultivation conditions during the presynthetic period. We discuss the hypothesis that derepressed genes mutate with a significantly higher rate than genes in the repressed state.

Adenine↗

PubMed2000

Homologous expression of recombinant cellobiose dehydrogenase in Phanerochaete chrysosporium.

Cellobiose dehydrogenase (CDH) is a novel extracellular hemoflavoenzyme from Phanerochaete chrysosporium and is produced only in cultures supplemented with cellulose. In this report, CDH from P. chrysosporium has been homologously expressed in cultures supplemented with glucose as the sole carbon source when no endogenous CDH is expressed. This was achieved by placing the cdh-1 gene under the control of the D-glyceraldehyde-3-phosphate dehydrogenase (gpd) promoter (1.1 kb) fused upstream of the ATG start codon of cdh-1. The gpd promoter-chd-1 construct was inserted into the multiple cloning site of the expression vector pOGI18, which contained the Schizophyllum commune ade5 as a selectable marker. The P. chrysosporium ade1 auxotrophic strain OGC107-1 was transformed with the pAGC1 construct, and the prototrophic transformants were assayed for CDH activity. Approximately 50% of the Ade(+) transformants exhibited CDH activity in the extracellular medium of stationary cultures. At least one of the transformants produced high levels (500-600 U/liter) of recombinant CDH (rCDH). Purification by ammonium sulfate precipitation, Sephacryl S-200 chromatography, and FPLC using a Mono-Q 5/5 column yielded homogeneous rCDH. Physical, spectral, and kinetic characteristics of purified homologously expressed rCDH were similar to those of wild-type CDH. This expression system will enable site-directed mutagenesis studies to be carried out on CDH.

2,6-Dichloroindophenol↗

PubMed1997

Synergistic increase in Ca2+ produced by A1 adenosine and muscarinic receptor activation via a pertussis-toxin-sensitive pathway in epithelial cells of the rabbit ciliary body.

The combined effects of adenosine and acetylcholine on the intracellular free-Ca2+ concentration in nonpigmented epithelial cells of the rabbit ciliary body were investigated using fura-2 fluorescence-ratio imaging. Acetylcholine (10 microM) by itself produced a modest increase in [Ca2+]i. Acetylcholine in combination with adenosine, or with the A1-specific agonists N6-cyclohexyl-adenosine, N6-cyclopentyl-adenosine and (R)-N6-(2-phenyl-1-methylethyl)-adenosine (0.1-1 microM), induced a massive increase in [Ca2+]i, which could be blocked by the A1-specific antagonist 8-cyclopentyl-1,3-dipropylxanthine. However, the A2-specific agonist 2-[(p-2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamide-ade nos ine and the antagonist 3,7-dimethyl-1-(2-propynyl)xanthine were without effect. Incubation of the tissue with pertussis toxin did not alter the response to ACh alone but eliminated the synergistic effect of adenosine (or of epinephrine). It was concluded that in the epithelial cells of the rabbit ciliary body, adenosine and epinephrine synergistically potentiate the rise in [Ca2+]i produced by ACh. This potentiation appears to occur via a pertussis-toxin-sensitive pathway, perhaps through G(i).

Acetylcholine↗

PubMed1999

C-H.O hydrogen bonds in minor groove of A-tracts in DNA double helices.

Analysis of available B-DNA type oligomeric crystal structures as well as protein-bound DNA fragments (solved using data with resolution <2.6 A) indicates that in both data sets, a majority of the (3'-Ade) H2..O2(3'-Thy/Cyt) distances in AA.TT and GA.TC dinucleotide steps, are considerably shorter than their values in a uniform fibre model, and are smaller than their optimum separation distance. Since the electropositive C2-H2 group of adenine is in close proximity of the electronegative keto oxygen atoms of both pyrimidine bases in the antiparallel strand of the double-helical DNA structures, it suggests the possibility of intra-base-pair as well as cross-strand C-H..O hydrogen bonds in the minor groove. The C2-H2..O2 hydrogen bonds within the A.T base-pairs could be a natural consequence of Watson-Crick pairing. However, the close cross-strand interactions between the bases at the 3'-ends of the AA.TT and GA.TC steps arise due to the local sequence-dependent geometry of these steps. While the base-pair propeller twist in these steps is comparable to the fibre model, some of the other local parameters such as base-pair opening angle and inter-base-pair slide show coordinated changes, leading to these shorter C2-H2..O2 distances. Hence, in addition to the well-known minor groove hydration, it appears that favourable C2-H2..O2 cross-strand interactions may play a role in imparting a characteristic geometry to AA.TT and GA.TC steps, as well as An.Tn and GAn.TnC tracts, which leads to a narrow minor groove in these regions.

Base Pairing↗

PubMed2002

Viral-mediated gene transfer to mouse primary neural progenitor cells.

Neural progenitor cells may provide for cell replacement or gene delivery vehicles in neurodegen-erative disease therapies. The expression of therapeutic proteins by neural progenitors would be enhanced by viral-mediated gene transfer, but the effects of several common recombinant viruses on primary progenitor cell populations have not been tested. To address this issue, we cultured cells from embryonic day 16-18 mouse brain in serum-free medium containing epidermal growth factor or basic fibroblast growth factor, and investigated how transduction with recombinant viral vectors affected maintenance and differentiation properties of progenitor cells. Neurosphere cultures were incubated with feline immunodeficiency virus (FIV), adeno-associated virus (AAV) or ade-noviral (Ad) constructs expressing either beta-galactosidase or enhanced green fluorescent protein at low multiplicity of infection. Nestin-positive neurospheres were regenerated after incubation of single progenitor cells with FIV, indicating that FIV-mediated gene transfer did not inhibit progenitor cell self-renewal. In contrast, adenovirus induced differentiation into glial fibrillary acidic protein (GFAP)-positive astrocytes. The AAV serotypes tested did not effectively transduce progenitor cells. FIV-transduced progenitors retained the potential for differentiation into neurons and glia in vitro, and when transplanted into the striatum of normal adult C57BL/6 mice differentiated into glia, or remained undifferentiated. In the presence of tumor cells, FIV-transduced progenitors migrated significantly from the injection site. Our results suggest that FIV-based vectors can transduce progenitor cell populations in vitro, with maintenance of their ability to differentiate into multiple cell types or to respond to injury within the central nervous system. These results hold promise for the use of genetically manipulated stem cells for CNS therapies.

Adenoviridae↗

PubMed1978

Fortification of soft drinks with protein from cottage cheese whey.

Cottage cheese whey protein concentrates, prepared by preconcentration by ultrafiltration followed by gel permeation to remove low molecular weight materials, have the solubility, stability and flavor that make them suitable for fortification of soft drinks and related products. These concentrates are characterized by high levels of "available" lysine and by amino acid compositions indicating good nutritional value. Carbonated beverages prepared with conventional beverage ingredients and containing up to 1% by weight of the total beverage of added whey protein maintained clarity, color, and flavor during 203 days storage at room temperature. Spray dried whey protein concentrates were incorporated without adverse effects into commercial "ade" type powders. Clarity of 1% protein solutions at pH 2--3.5 was not impaired by heating for 6h at 80 degree, but some structural change occurred since an average of 37% of the protein precipitated on shifting pH to 4.7. Increased stability against heat denaturation under acidic conditions was conferred by some soft drink ingredients. Added sucrose reduced protein denaturation by 1/2 but sodium saccharin had no effect. The type of acid used also altered protein denaturation rate. While properly isolated whey protein concentrates have functional properties necessary for soft drink fortification, feasibility of use will depend upon cost.

Beverages↗

PubMed1978

8-hydroxyquinoline inhibition of DNA synthesis and intragenic recombination during yeast meiosis.

Complete inhibition of sporulation was observed in two strains of Saccharomyces cerevisiae to which 8-hydroxyquinoline was added at a final concentration of 5 microgram/ml during the initial 4 to 6 h of sporulation. The cells were most sensitive to the inhibitor during 4 to 6 interval beginning at approximately 2 h (T2). Its addition during that interval resulted in 70 to 80% lethality in strain 4579 and about 40% in API at T24. When present from T0 onward, 5 microgram/ml of 8-hydroxyquinoline severely inhibited premeiotic DNA replication and reduced the frequency of intragenic recombination at the ade 2 and leu 2 loci by 70 and 100%, respectively, relative to control cultures which did not have the inhibitor present. During the period when the cells were most sensitive, the incorporation of 14C-leucine into protein and 14C-adenine into RNA was not inhibited nor was the polysome content affected. At 150 microgram/ml of inhibitor, incorporation of labeled precursors into RNA and protein were inhibited and the percentage of active ribosomes was reduced by 35% within 45 min, but neither transcription or translation appeared to be completely inhibited at this concentration of the inhibitor.

Cell Cycle↗

PubMed1995

Identification of the heterothallic mutation in HO-endonuclease of S. cerevisiae using HO/ho chimeric genes.

HO-endonuclease initiates a mating-type switch in the yeast S. cerevisiae by making a double-strand cleavage in the DNA of the mating-type gene, MAT. Heterothallic strains of yeast have a stable mating type and contain a recessive ho allele. Here we report the sequence of the ho allele; ho has four point mutations all of which encode for substitute amino acids. The fourth mutation is a leucine to histidine substitution within a presumptive zinc finger. Chimeric HO/ho genes were constructed in vivo by converting different parts of the sequence of the genomic ho allele to the HO sequence by gene conversion. HO activity was assessed by three bioassays: a mating-type switch, extinction of expression of an a-specific reporter gene, and the appearance of Canr Ade- papillae resulting from excision of an engineered Ty element containing the HO-endonuclease target site and a SUP4 degrees gene. We found that the replacement of the fourth point mutation in ho to the HO sequence restored HO activity to the chimeric endonuclease.

Alleles↗

PubMed1985

Replicating instabilities in yeast: occurrence in different mutational systems.

Following mutagenesis of yeast cells with nitrosoguanidine, primary mosaic colonies exhibiting prototrophic/auxotrophic phenotypes were obtained. Upon replating of these primary mosaics, numerous secondary mosaics were present in the progeny. This study shows that replicating instabilities occur at many different loci within the Schizosaccharomyces pombe genome. In addition, the ade-1 gene of Saccharomyces cerevisiae (causing red pigmentation) was used to show that the phenomenon also occurs in this yeast.

Ascomycota↗

PubMed1982

Construction of a Schizosaccharomyces pombe gene bank in a yeast bacterial shuttle vector and its use to isolate genes by complementation.

A gene bank of partial Sau3A restriction fragments of S. pombe DNA has been constructed in the plasmid vector, pDB248', which is capable of high frequency transformation of S. pombe. Procedures are described which enable plasmids to be recovered from S. pombe by their reintroduction into E. coli. These methods have been used to detect the S. pombe genes lys 1+, ade 6+ and his 2+ in the gene bank by complementation of mutant gene functions, and to physically isolate the lys 1+ gene.

Ascomycota↗