Biomonitoring of Human Population Exposure to Environmental Genotoxic Chemicals: the EEC Project.
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Blood Cells↗
Biomedical subjects
R Waters
Publications and source records attributed to R Waters.
Differential repair of UV damage in Saccharomyces cerevisiae is cell cycle dependent.
In the yeast Saccharomyces cerevisiae the transcriptionally active MAT alpha locus is repaired preferentially to the inactive HML alpha locus after UV irradiation. Here we analysed the repair of both loci after irradiating yeast cells at different stages of the mitotic cell cycle. In all stages repair of the active MAT alpha locus occurs at a rate of 30% removal of dimers per hour after a UV dose of 60 J/m2. The inactive HML alpha is repaired as efficiently as MAT alpha following irradiation in G2 whereas repair of HML alpha is less efficient in the other stages. Thus differential repair is observed in G1 and S but not in G2. Apparently, in G2 a chromatin structure exists in which repair does not discriminate between transcriptionally active and inactive DNA or, alternatively, an additional repair mechanism might exist which is only operational during G2.
Blotting, Southern↗
Formal axillary dissection.
Formal axillary dissection is a precise anatomical procedure by which the lymphatic contents of the axilla are removed en bloc. It is used as both a staging and a therapeutic procedure for carcinoma of the breast, and as a therapeutic or palliative procedure for established axillary metastases.
Axilla↗
DNA alkylations and mutation after exposure to ethyl methanesulphonate in mammalian cell lines routinely used in mutagenicity testing.
DNA ethylations were measured in four mammalian cell lines, Chinese hamster ovary CHO, mouse lymphoma L5178Y t k+/-, human lymphoblastoid TK6 and Chinese hamster V79, following exposure to [3H]ethyl methanesulphonate. Concurrent estimates of cytotoxicity and gene mutation were also carried out. Total DNA-binding and relative levels of ethylation at N-7 guanine (N-7G), O6 guanine (O6G) and N-3 adenine (N-3A) were essentially the same in all four cell lines. Differences in response to EMS between the cell lines, namely the greater cytotoxicity in TK6 cells, would therefore appear to reflect subsequent handling of the DNA lesions, rather than different levels of DNA ethylation in the cell lines.
Adenine↗
Transfer of the pronator teres tendon to the tendons of the flexor digitorum profundus in tetraplegia.
In eleven patients who had traumatic tetraplegia, the pronator teres tendon was transferred to the flexor digitorum profundus tendons to restore active flexion of the fingers. At the same time, in ten of these patients the tendon of the brachioradialis was transferred to the tendon of the flexor pollicis longus, and in the eleventh patient the brachioradialis tendon was transferred to the tendon of the flexor digitorum superficialis of the small finger, to restore pinch. The average time between injury and operation was thirty-four months. The average length of follow-up after operation was thirty-four months. Ten patients gained functional active flexion of the fingers, and they reported improved performance of activities of daily living. When the wrist was in 30 degrees of extension, the average active grasp strength was twenty-one millimeters of mercury and the average key-pinch strength was 2.2 kilograms. The average active flexion of the fingers from the resting position, measured from the tip of the finger to the distal palmar crease, was 1.5 centimeters. Only one patient did not gain active flexion of the fingers. Of the entire group, this patient had the least function of the hand on preoperative evaluation; retrospectively, he seemed to be a poor candidate for operation, since the strength of the pronator teres muscle and the sensibility of the hand were insufficient for useful function. We concluded that, in selected tetraplegic patients, transfer of the pronator teres tendon to the flexor digitorum profundus tendons provides useful active flexion of the fingers.
Adult↗
Studies on the ability of smoke from different types of cigarettes to induce DNA single-strand breaks in cultured human cells.
In this paper we report preliminary studies using alkaline elution to examine the incidence of DNA-strand breakage in human lung cells exposed to smoke/phosphate-buffered saline generated from cigarettes of different tar contents and filter status. The majority of the DNA breaks induced were abolished by catalase indicating a role for active oxygen species. The incidence of breaks did not correlate with the tar content of the cigarettes. The presence of a filter in the cigarette reduced the TPM concentration of the mainstream smoke but did not reduce the number of single-strand breaks occurring in DNA after exposure to smoke/PBS. This last parameter was however reduced if the filter was ventilated.
Catalase↗
The repair of identified large DNA adducts induced by 4-nitroquinoline-1-oxide in normal or xeroderma pigmentosum group A human fibroblasts, and the role of DNA polymerases alpha or delta.
4-Nitroquinoline-1-oxide (4NQO) reacts with DNA primarily at the N2 and C8 of guanosine, with a small percent of reaction at the N6 of adenosine. In human cells it has been unclear whether or not all 4NQO-induced adducts are removed by a nucleotide excision repair mechanism. In this paper we demonstrate that the inhibitor of DNA polymerases alpha and delta, aphidicolin, blocks the repair of all 4NQO adducts. Hence excision repair must operate on all of these lesions. After 4NQO the residual excision repair seen in a xeroderma pigmentosum group A cell line virtually totally defective in UV repair was 40-60% of that in normal cells. Therefore there must be some differences between the excision repair operating on UV as opposed to 4NQO-induced DNA damage.
4-Nitroquinoline-1-oxide↗
Orofacial infection of athymic mice with defined mixtures of acyclovir-susceptible and acyclovir-resistant herpes simplex virus type 1.
Infection of athymic mice with defined populations of acyclovir-susceptible (thymidine kinase [TK]-positive) and acyclovir-resistant (TK-deficient or TK-altered) herpes simplex virus type 1 strains was used to simulate herpetic skin disease of the immunocompromised host. In vitro characterization of the defined virus mixtures revealed that the dye uptake method was quite sensitive in the detection of small amounts (3 to 9%) of acylovir-resistant virus. Mice infected with homogeneous virus populations exhibited a good correlation between clinical response and the in vitro drug susceptibility of the infecting virus. Animals infected with defined mixtures of viruses exhibited varied patterns of infection and responses to acyclovir treatment. However, disease severity was useful in predicting the TK phenotype of virus recovered from lesions. Pathogenic, TK-altered virus was responsible for progressive disease in animals receiving low-dose (0.25-mg/ml) prophylactic acyclovir or high-dose (1.25-mg/ml) delayed therapy. Although this mutant was recovered infrequently, it was responsible for clinically significant disease in the animals from which it was isolated.
Acyclovir↗
Induction and repair of DNA strand breaks and 1-beta-D-arabinofuranosylcytosine-detectable sites in 40-75 kVp X-irradiated compared to 60Co gamma-irradiated human cell lines.
We have compared the initial yield and subsequent enzymatic repair of DNA strand breaks and 1-beta-D-arabinofuranosylcytosine (araC)-detectable sites in cultured human cell lines after irradiation with soft (40-75 kVp) X rays and hard (60Co) gamma rays, two forms of low-LET radiation whose average ionization densities differ by 15-fold (i.e., approximately 4.5 keV/mu and approximately 0.3 keV/mu, respectively). Incubation of X- or gamma-irradiated cell cultures in the presence of araC resulted in the accumulation of DNA single-strand interruptions, as measured by conventional velocity sedimentation analysis in alkaline sucrose gradients. Since the drug is a selective inhibitor of DNA polymerase alpha, this observation implicates polymerase alpha in the repair of radiogenic damage. Specifically, DNA repair analysis in X-ray-treated cells suggested that polymerase alpha is a key participant in the repair of a distinct, albeit structurally undefined, class of radioproducts [presumably a combination of double-strand breaks and alkali-stable lesions (e.g., modified base/sugar residues and DNA crosslinks)], but takes little, if any, part in the restitution of single-strand breaks (whether frank scissions or alkali-labile bonds) induced by ionizing radiation. Accordingly, the drug did not significantly inhibit the repair of DNA damage in cultures exposed to less than or equal to 100 Gy of gamma radiation. A remarkable difference was evident with respect to the absolute yields of these two major classes of DNA injury--that is, araC-detectable sites and single-strand breaks--depending on the type of radiation administered. For the same dose, the level of araC-detectable sites found in cells treated with gamma rays (less than or equal to 150 Gy) was as much as 3.4 times lower than that observed in X-ray-exposed cells (i.e., one site per 1,155 and 335 eV, respectively). In contrast, the number of strand breaks induced by gamma rays was approximately 2.3-fold higher than that produced by X rays (one break per 27 and 61 eV, respectively). Assuming that, among other conditions, the relative biological effectiveness of the comparatively densely ionizing soft X rays is roughly twice that of the sparsely ionizing hard gamma rays, our data strongly imply that those radioproducts which are manifested as araC-detectable sites may be approximately 45 times more deleterious, on a per lesion basis, than those observed as single-strand breaks.
Cell Line↗
A complex pattern of sensitivity to simple monofunctional alkylating agents exists amongst the rad mutants of Saccharomyces cerevisiae.
The radiation-sensitive rad mutants of the yeast Saccharomyces cerevisiae exhibit a complex pattern of sensitivity to simple monofunctional alkylating agents. The RAD1, RAD2, RAD4 and RAD14 genes of the RAD3 epistasis group are implicated in the repair of ethylations to DNA. The RAD3, RAD10 and RAD16 genes of this group are not involved. The RAD4 and RAD14 genes have a particular role in repair following exposure to those ethylating agents that preferentially alkylate oxygen, but not to those that preferentially ethylate nitrogen. The RAD1 and RAD2 genes are involved in the repair of damage induced by all the ethylating agents used except EMS. The mutants in this group that are sensitive to ENU were not sensitive to MNU, suggesting that nucleotide excision operates on ethylations but not on methylations. In the RAD6 group, the RAD6 and RAD18 genes are involved in DNA repair after exposure to all the alkylating agents tested, whereas RAD8 appears to have a role in the repair of O-alkylations but not N-alkylations. RAD9 operates in the repair of methylations and ethylations, but does not influence events after exposure to EMS. In the RAD52 group, the mutants tested were sensitive to ENU and DES. Thus some members of all three epistasis groups are involved in the repair of alkylations to DNA.
Alkylating Agents↗
The response to DNA damage induced by 4-nitroquinoline-1-oxide or its 3-methyl derivative in xeroderma pigmentosum fibroblasts belonging to different complementation groups: evidence for different epistasis groups involved in the repair of large adducts in human DNA.
The data in this paper show that when the inhibition of growth is measured, xeroderma pigmentosum (XP) complementation groups A, G and D are very sensitive to 4-nitroquinoline-1-oxide (4NQO), whereas only XP groups G and D are very sensitive to 3-methyl-4NQO (3me4NQO). Cells belonging to XP-C group are not particularly sensitive to either agent. Thus there are different epistasis groups for the excision repair of DNA adducts induced by these agents as opposed to the repair of u.v. damage. DNA polymerase alpha is involved in the repair of 4NQO-induced lesions because aphidicolin blocks their repair. XP cells from all the above groups are defective to some extent in this repair. The degree of repair defectiveness follows that seen after u.v., with even the XP-C cell line used having reduced repair (despite the fact that the inhibition of growth by 4NQO in this cell line was not markedly different from normal). Aphidicolin did not induce breaks in the normal or XP cell lines exposed to 3me4NQO, thus the repair of lesions induced by 3me4NQO does not involve DNA polymerase alpha in any of the cell lines. Finally, catalase reduces the alkaline labile lesions induced by 4NQO, but not 3me4NQO, suggesting the latter agent does not induce substantial amounts of DNA damage by the generation of radicals.
4-Nitroquinoline-1-oxide↗
Posterior cervical fusion with local anesthesia. The awake patient as the ultimate spinal cord monitor.
A technique is described for posterior cervical stabilization with wire and fusion using iliac crest bone graft, performed under local anesthesia. Thirty-four consecutive cases performed at Rancho Los Amigos Medical Center are reviewed. In patients with unstable cervical spines and variable degrees of neurologic injury, posterior stabilization and fusion using local anesthesia allows the patient to interact with the surgeon during crucial moments of spinal manipulation. The technique is well tolerated by patients, and no untoward complications have occurred with use of this technique.
Adolescent↗
DNA ethylations induced by ethylnitrosourea in the wild type, cdc4 and cdc7 strains of Saccharomyces cerevisiae.
The experiments reported here have investigated the induction of ethylations to DNA in yeast cells exposed to the chemical mutagen ethylnitrosourea. A similar level of alkylation was seen at the N7 and O6 of guanine and at the N3 of adenine in either log phase cells or in temperature-sensitive cdc4 and cdc7 cells growth arrested at their specific G1 positions. Hence the changes in chromosome structure associated with the above cdc phenotypes do not modify the amount of DNA damage induced by ethylnitrosourea.
DNA Damage↗
Systemic absorption of 14C-glutaraldehyde from glutaraldehyde-treated pulpotomy sites.
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Aldehydes↗
Benzyl chloride and 4-chloromethylbiphenyl induced DNA damage and its repair in excision-deficient (XP group A) or -proficient human cells.
Benzyl chloride (BC) and 4-chloromethylbiphenyl (4CMB) induce a class of alkaline-stable DNA damage in human cells which, like UV-induced pyrimidine dimers, undergoes repair at a slow rate by an excision-repair pathway which can be inhibited by cytosine arabinoside (araC). In the present study, in an attempt to clarify whether BC and 4CMB are UV-like agents, the excision-deficient xeroderma pigmentosum complementation group A fibroblasts and excision-proficient human alveolar tumour cells (A549) were exposed to various doses of these compounds prior to monitoring the inhibition of cell growth, DNA damage and DNA repair. The data indicate that such XP fibroblasts repair BC- and 4CMB-induced DNA damage at a normal rate, which suggests that the alkaline-stable DNA adducts induced by these chloromethyl compounds and the UV-induced pyrimidine dimers are processed by distinct excision-repair mechanisms in human cells.
Benzyl Compounds↗
Brachioradialis to flexor pollicis longus tendon transfer for active lateral pinch in the tetraplegic.
Seventeen hands in 15 patients with posttraumatic tetraplegia had transfers of the brachioradialis tendon to the flexor pollicis longus in an attempt to create an active lateral pinch. In addition, interphalangeal joint fixation with a Moberg screw was performed in 16 thumbs and tenodesis of the extensor pollicis longus and brevis tendons to the metacarpal was performed in 11 patients. Average patient age was 32 years, time from onset of tetraplegia to operation was 5.3 years, and postoperative follow-up was 2.3 years. Functional improvement was noted in 15 hands and 80% of the patients could name at least four activities of daily living that were now possible or made more efficient as a result of surgery. With the elbow flexed to 90 degrees, the average lateral pinch was 3.9 pounds with the wrist extended 30 degrees, 4 pounds with the wrist in the neutral position, and 2.3 pounds with the wrist flexed 30 degrees. There was a direct correlation between pinch strength and the amount of residual triceps and wrist extensor strength.
Activities of Daily Living↗
Defective repair of a class of 4NQO-induced alkali-labile DNA lesions in xeroderma pigmentosum complementation group A fibroblasts.
Normal human or xeroderma pigmentosum complementation group A (XP-A) fibroblasts were exposed to various concentrations of either 4-nitroquinoline 1-oxide (4NQO) or its 3-methyl derivative, and the rates of repair of the alkali-labile lesions induced in DNA by each agent were monitored over a period of 24 h post-treatment incubation. The data indicate that 4NQO induces at least two major classes of alkali-labile lesions into human DNA; one class disappears rapidly from the DNA of both normal and XP-A fibroblasts, while the other class undergoes repair at a relatively slow rate in normal cells, but is not removed at all in the excision-deficient cells. Methylation of 4NQO at the 3-position appears to abolish the induction of the latter class of alkali-labile lesions, whereas the rapidly removed lesions are still being induced.
4-Hydroxyaminoquinoline-1-oxide↗