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PubMed1988

The role of the priming fluid in the metabolic response to cardiopulmonary bypass in children of less than 15 kg body weight undergoing open-heart surgery.

The major metabolic response to open-heart surgery using cardiopulmonary bypass has been shown in adults to be modified by the components of the pump priming fluid. This effect is likely to be more significant in children. Data on 29 children less than 15 kg body weight are presented. Patients were randomised to receive a prime containing one of three crystalloid priming fluids: 100% Hartmann's (H), 50% Hartmann's + 50% 5%-Dextrose (HD), or 100% Plasmalyte 148 (P). The remainder of the prime was CPD stored blood and the prime was buffered with sodium bicarbonate. Severe hyperglycaemia 22.4 +/- 1.3 mmol/l occurred during bypass in the HD group but moderate hyperglycaemia occurred in the other prime groups. Hyperlactataemia occurred in all prime groups during bypass and was highest in the H prime group at 3.9 +/- 0.4 mmol/l. These changes in intermediary metabolites were only partly explained by the crystalloid components of the priming fluid. A subsiduary study revealed the important contribution of CPD stored blood to those intermediary metabolite concentrations. Therefore, the well recognised changes in intermediary metabolites as components of the metabolic response to surgery, namely hyperglycaemia and hyperlactataemia were augmented by the composition of the priming fluids. In addition, CPD stored blood and the sodium bicarbonate buffer increased the sodium concentration of the prime to hypernatraemic levels in both the H and P groups which caused an increase in sodium concentration during bypass. Therefore important changes during bypass occur as a direct result of the individual components of the priming fluid. These changes may result in osmolal flux, hyperglycaemia and hyperlactataemia, all of which have been reported to be potentially harmful.

Blood Glucose↗

PubMed2000

Prognostic assessment of sonography and tumor volumetry in advanced cancer of the head and neck by use of doppler ultrasonography.

OBJECTIVE: The objective of this trial was to examine the degree of tumor vascularity in lymph node metastases as depicted by computer-assisted color Doppler sonography and the tumor volumes associated with prognosis in carcinomas of the oropharynx and hypopharynx after primary radiochemotherapy. PATIENTS AND METHODS: In a prospective trial, 25 patients with advanced squamous cell carcinomas of the oropharynx and hypopharynx (stage IV UICC 1997) were treated with radiochemotherapy. The color Doppler findings were quantified with a computer-assisted protocol that quantitatively describes color Doppler images by the relative color pixel density (CPD). As important prognostic cofactor, total tumor volume (TTV) was calculated from CT sections and related to the degree of vascularity. RESULTS: Low CPD in neck metastases showed a correlation with better overall survival. A high-CPD group and a high-TTV group (median survival 10.1 months) were determined and were compared with all other CPD/TTV combinations (median survival 28.4 months); the difference in survival was significant (P = 0.002). CONCLUSION: The results indicate that high tumor vascularity in combination with high TTV indicates a particularly bad prognosis in patients treated with primary radiochemotherapy for head and neck cancer.

Adult↗

PubMed2005

Distinct mechanisms of cis-syn thymine dimer bypass by Dpo4 and DNA polymerase eta.

UV-light-induced cyclobutane pyrimidine dimers (CPDs) present a severe block to synthesis by replicative DNA polymerases (Pols), whereas Poleta promotes proficient and error-free replication through CPDs. Although the archael Dpo4, which, like Poleta, belongs to the Y family of DNA Pols, can also replicate through a CPD, it is much less efficient than Poleta. The x-ray crystal structure of Dpo4 complexed with either the 3'-thymine (T) or the 5' T of a cis-syn TT dimer has indicated that, whereas the 3' T of the dimer forms a Watson-Crick base pair with the incoming dideoxy ATP, the 5' T forms a Hoogsteen base pair with the dideoxy ATP in syn conformation. Based upon these observations, a similar mechanism involving Hoogsteen base pairing of the 5' T of the dimer with the incoming A has been proposed for Poleta. Here we examine the mechanisms of CPD bypass by Dpo4 and Poleta using nucleotide analogs that specifically disrupt the Hoogsteen or Watson-Crick base pairing. Our results show that both Dpo4 and Poleta incorporate dATP opposite the 5' T of the CPD via Watson-Crick base pairing and not by Hoogsteen base pairing. Furthermore, opposite the 3' T of the dimer, the two Pols differ strikingly in the mechanisms of dATP incorporation, with Dpo4 incorporating opposite an abasic-like intermediate and Poleta using the normal Watson-Crick base pairing. These observations have important implications for the mechanisms used for the inefficient vs. efficient bypass of CPDs by DNA Pols.

Base Pairing↗

PubMed2000

UV-damage-mediated induction of homologous recombination in Arabidopsis is dependent on photosynthetically active radiation.

Plants are continuously subjected to UV-B radiation (UV-B; 280-320 nm) as a component of sunlight causing damage to the genome. For elimination of DNA damage, a set of repair mechanisms, mainly photoreactivation, excision, and recombination repair, has evolved. Whereas photoreactivation and excision repair have been intensely studied during the last few years, recombination repair, its regulation, and its interrelationship with photoreactivation in response to UV-B-induced DNA damage is still poorly understood. In this study, we analyzed somatic homologous recombination in a transgenic Arabidopsis line carrying a beta-glucuronidase gene as a recombination marker and in offsprings of crosses of this line with a photolyase deficient uvr2-1 mutant. UV-B radiation stimulated recombination frequencies in a dose-dependent manner correlating linearly with cyclobutane pyrimidine dimer (CPD) levels. Genetic deficiency for CPD-specific photoreactivation resulted in a drastic increase of recombination events, indicating that homologous recombination might be directly involved in eliminating CPD damage. UV-B irradiation stimulated recombination mainly in the presence of photosynthetic active radiation (400-700 nm) irrespective of photolyase activities. Our results suggest that UV-B-induced recombination processes may depend on energy supply derived from photosynthesis.

Arabidopsis↗

PubMed2000

Nucleotide excision repair of the 5 S ribosomal RNA gene assembled into a nucleosome.

A-175-base pair fragment containing the Xenopus borealis somatic 5 S ribosomal RNA gene was used as a model system to determine the effect of nucleosome assembly on nucleotide excision repair (NER) of the major UV photoproduct (cyclobutane pyrimidine dimer (CPD)) in DNA. Xenopus oocyte nuclear extracts were used to carry out repair in vitro on reconstituted, positioned 5 S rDNA nucleosomes. Nucleosome structure strongly inhibits NER at many CPD sites in the 5 S rDNA fragment while having little effect at a few sites. The time course of CPD removal at 35 different sites indicates that >85% of the CPDs in the naked DNA fragment have t(12) values <2 h, whereas <26% of the t(12) values in nucleosomes are <2 h, and 15% are >8 h. Moreover, removal of histone tails from these mononucleosomes has little effect on the repair rates. Finally, nucleosome inhibition of repair shows no correlation with the rotational setting of a 14-nucleotide-long pyrimidine tract located 30 base pairs from the nucleosome dyad. These results suggest that inhibition of NER by mononucleosomes is not significantly influenced by the rotational orientation of CPDs on the histone surface, and histone tails play little (or no) role in this inhibition.

Animals↗

PubMed2003

Genetic and biochemical analysis of the functional domains of yeast tRNA ligase.

Yeast tRNA ligase (Trl1) converts cleaved tRNA half-molecules into spliced tRNAs containing a 2'-PO4, 3'-5' phosphodiester at the splice junction. Trl1 performs three reactions: (i) the 2',3'-cyclic phosphate of the proximal fragment is hydrolyzed to a 3'-OH, 2'-PO4 by a cyclic phosphodiesterase (CPD); (ii) the 5'-OH of the distal fragment is phosphorylated by an NTP-dependent polynucleotide kinase; and (iii) the 3'-OH, 2'-PO4, and 5'-PO4 ends are sealed by an ATP-dependent RNA ligase. Trl1 consists of an N-terminal adenylyltransferase domain that resembles T4 RNA ligase 1, a central domain that resembles T4 polynucleotide kinase, and a C-terminal CPD domain that resembles the 2H phosphotransferase enzyme superfamily. Here we show that all three domains are essential in vivo, although they need not be linked in the same polypeptide. We identify five amino acids in the adenylyltransferase domain (Lys114, Glu266, Gly267, Lys284, and Lys286) that are essential for Trl1 activity and are located within motifs I (114KANG117), IV (266EGFVI270), and V (282FFKIK286) that comprise the active sites of DNA ligases, RNA capping enzymes, and T4 RNA ligases 1 and 2. Mutations K404A and T405A in the P-loop (401GXGKT405) of the central kinase-like domain had no effect on Trl1 function in vivo. The K404A and T405A mutations eliminated ATP-dependent kinase activity but preserved GTP-dependent kinase activity. A double alanine mutant in the P-loop was lethal in vivo and abolished GTP-dependent kinase activity. These results suggest that GTP is the physiological substrate and that the Trl1 kinase has a single NTP binding site of which the P-loop is a component. Two other mutations in the central domain were lethal in vivo and either abolished (D425A) or severely reduced (R511A) GTP-dependent RNA kinase activity in vitro. Mutations of the signature histidines of the CPD domain were either lethal (H777A) or conferred a ts growth phenotype (H673A).

Amino Acid Sequence↗

PubMed2005

Reaction of ferric cytochrome P450cam with peracids: kinetic characterization of intermediates on the reaction pathway.

Reactions of substrate-free ferric cytochrome P450cam with peracids to generate Fe=O intermediates have previously been investigated with contradictory results. Using stopped-flow spectrophotometry, the reaction with m-chloroperoxybenzoic acid demonstrated an Fe(IV)=O + porphyrin pi-cation radical (Cpd I) (Egawa, T., Shimada, H., and Ishimura, Y. (1994) Biochem. Biophys. Res. Commun. 201, 1464-1469). By contrast, with peracetic acid, Fe(IV)=O plus a tyrosyl radical were observed by freeze-quench Mossbauer and EPR spectroscopy (Schunemann, V., Jung, C., Trautwein, A. X., Mandon, D., and Weiss, R. (2000) FEBS Lett. 479, 149-154). Our detailed kinetic studies have resolved these contradictory results. At pH >7, a significant fraction of Cpd I is formed transiently, whereas at low pH only a species with a Soret band at 406 nm, presumably Fe(IV)=O + tyrosyl radical, is observed. Evidence for formation of an acylperoxo complex en route to Cpd I was obtained. Because of rapid heme destruction, steps subsequent to formation of the highly oxidized forms could not be fully characterized. Heme destruction was avoided by including peroxidase substrates (e.g. guaiacol), which were oxidized to characteristic peroxidase products as the Fe(III)-P450 was regenerated. Addition of ascorbate to either of the high valent species also reforms the Fe(III) state with only a small loss of heme absorbance. These results indicate that typical peroxidase chemistry occurs with P450cam and offer an explanation for the contrasting results reported earlier. The delineation of improved conditions (pH, temperature, choice of peracid) for generating highly oxidized species with P450cam should be valuable for their further characterization.

Camphor 5-Monooxygenase↗

PubMed2004

Accessible Web design.

As part of the Institute of Medical Illustrators' (IMI) scheme for continuing professional development (CPD), worksheets will be published at regular intervals in this Journal. These are designed to provide the members of IMI with a structured CPD activity that offers one way to earn credits. It is recognized that this worksheet requires some time spent undertaking the exercises. This activity has been tested, and hours have been allocated to individual tasks (see clocks), but these are intended only as a guide. The answers to the questions, along with any notes and reflections you make or other publications you find, should be kept in your CPD portfolio.

Computer Literacy↗

PubMed2002

Smoking reduction practices among African American smokers.

Despite smoking fewer cigarettes per day than Caucasians, African Americans bear a disproportionate share of health consequences of smoking. Because the risk of many tobacco-related diseases is dose-dependent, smoking reduction has been suggested as a method to reduce harm for smokers. Little information exists about behavioral smoking-reduction strategies and whether such strategies result in smoking fewer cigarettes. We conducted a survey of 484 African American smokers classified as occasional, light, moderate, and heavy smokers. The survey examined sociodemography, smoking characteristics, and eight smoking reduction strategies, including intentional limiting of smoking, smoking less than half of a cigarette, setting a daily limit for smoking, changing cigarette brand, reducing number of cigarettes, smoking only on some days, switching to a lighter tar cigarette, and not inhaling deeply. Compared to moderate and heavy smokers, occasional and light smokers were more likely to have engaged in most of these strategies. Smokers who used >or= 4 strategies on average smoked 11 cigarettes per day (cpd), compared to 14 cpd and 18 cpd for those who used 1 to 3 strategies and no strategies respectively (p <.0001). After analyses controlled for age, gender, and education, the number of smoking reduction strategies utilized was a significant predictor of smoking 10 or fewer cigarettes per day. This study provides evidence that African American smokers who engaged in multiple smoking reduction strategies smoked fewer cigarettes per day. Smokers not interested in quitting but willing to reduce their smoking should be encouraged to utilize a variety of smoking reduction strategies.

Adult↗

PubMed1985

[Protein and amino acid metabolism in the digestive tract of growing young bulls. 4. Apparent digestibility of NH3-free raw protein reaching the duodenum and critical evaluation of apparently digestible raw protein].

The experimental determination of the apparent digestibility (AD) of the NH3-free crude protein at the duodenum (NH3 fr. CPD) showed a value of 65.7% at a standard error of +/- 3.6% for the section of the digestive tract between proximal duodenum and end of rectum. This standard error can only be insignificantly diminished due to the existing relation between AD of NH3 fr. CPD in dependence on the CP concentration in the ration (y = 56.4 + 0.598 x +/- 3.17; r = 0.501xx) so that this relation has no practical significance. The criticism of AD CP is correct from a point of view of digestion physiology. There is only agreement between AD PC and AD NH3 fr. CPD in a CP concentration range between 12.5 and 14.0% CP in the DM, which, however, applies to a large range of the production sphere in the rearing of young bulls. It excludes, however, the low live weight range with high live weight gains.

Amino Acids↗

PubMed1993

Hematopoietic progenitor content of fetal cord blood collected using citrate-phosphate-dextrose: influence of holding temperature and delays.

Storage of unseparated fetal cord blood collected into citrate-phosphate-dextrose (CPD) for 48 hours has been studied using progenitor cell assays [plasma clot technique with plasma-conditioned medium, erythropoietin (EPO), erythropoietin + IL-3 as growth factors]; collected fetal blood volume was low [61 +/- 4 ml, mean +/- 95% confidence interval (CI)]. The CFU-GM concentration in total cord blood was 2460 +/- 1476 CFU-GM/ml, comparable to normal bone marrow collected into medium RPMI + heparin (2350 +/- 1258); 2 of 12 samples contained fewer than 10(3) CFU-GM. Storage of unseparated cord blood CFU-GM in CPD was better at 4 degrees C (rapid decrease at day (D) 2 from 15 +/- 9 x 10(4) at D0; 14 +/- 11 x 10(4) at D1 to 6 +/- 4 x 10(4) at (D2) than at 22 degrees C (strong decrease since D1: 5 +/- 4 x 10(4) CFU-GM). The CFU-GEMM content remained steady at 4 degrees C: from 16 +/- 16 x 10(4) at D0 to 18 +/- 16 at D2. Cryopreservation and thawing of unfractionated cord blood at D0 did not affect the CFU-FM cloning rates. Whether mature progenitors are more affected than stem cells by storage in CPD remains to be determined.

Adult↗

PubMed2000

Cyclobutane pyrimidine dimers form preferentially at the major p53 mutational hotspot in UVB-induced mouse skin tumors.

The most prevalent DNA lesion induced by UV irradiation is the cyclobutane pyrimidine dimer (CPD) which forms at positions of neighboring pyrimidines. In mouse skin tumors induced by irradiation with UVB (280-320 nm) lamps or solar UV simulators, a major mutational hotspot occurs at codon 270 (Arg-->Cys) involving a sequence change from 5'-TCGT to 5'-TTGT. We have shown previously that CPD formation by UVB or sunlight is enhanced up to 10-fold at 5'-CCG and 5'-TCG sequences due to the presence of 5-methylcytosine bases. Sequence analysis showed that the CpG at codon 270 is methylated in mouse epidermis at a level of approximately 85%. Irradiation of mouse skin or mouse cells in culture produced the strongest CPD signal within exon 8 at the 5'-TCG sequence which is part of codon 270. Time course experiments showed that CPDs at this particular sequence persist longer than at several neighboring positions. The data suggest that formation of CPDs is responsible for induction of the major p53 mutational hotspot in UV-induced mouse skin tumors.

Animals↗

PubMed1999

Tight correlation between inhibition of DNA repair in vitro and transcription factor IIIA binding in a 5S ribosomal RNA gene.

UV-induced photoproducts (cyclobutane pyrimidine dimers, CPDs) in DNA are removed by nucleotide excision repair (NER), and the presence of transcription factors on DNA can restrict the accessibility of NER enzymes. We have investigatigated the modulation of NER in a gene promoter using the Xenopus transcription factor IIIA (TFIIIA)-5S rDNA complex and Xenopus oocyte nuclear extracts. TFIIIA alters CPD formation primarily in the transcribed strand of the 50 bp internal control region (ICR) of 5S rDNA. During NER in vitro, CPD removal is reduced at most sites in both strands of the ICR when TFIIIA is bound. Efficient repair occurs just outside the TFIIIA-binding site (within 10 bp), and in the absence of 5S rRNA transcription. Interestingly, three CPD sites within the ICR [+56, +75 (transcribed strand) and +73 (non-transcribed strand)] are repaired rapidly when TFIIIA is bound, while CPDs within approximately 5 bases of these sites are repaired much more slowly. CPDs at these three sites may partially displace TFIIIA, thereby enabling rapid repair. However, TFIIIA is not completely displaced during NER, at least at sites outside the ICR, even though the NER complex could be sterically hindered by TFIIIA. Such inefficient repair of transcription factor binding sites could increase mutation frequency in regulatory regions of genes.

Animals↗

PubMed2000

Misinsertion and bypass of thymine-thymine dimers by human DNA polymerase iota.

Human DNA polymerase iota (pol(iota)) is a recently discovered enzyme that exhibits extremely low fidelity on undamaged DNA templates. Here, we show that poliota is able to facilitate limited translesion replication of a thymine-thymine cyclobutane pyrimidine dimer (CPD). More importantly, however, the bypass event is highly erroneous. Gel kinetic assays reveal that pol(iota) misinserts T or G opposite the 3' T of the CPD approximately 1.5 times more frequently than the correct base, A. While pol(iota) is unable to extend the T.T mispair significantly, the G.T mispair is extended and the lesion completely bypassed, with the same efficiency as that of the correctly paired A. T base pair. By comparison, pol(iota) readily misinserts two bases opposite a 6-4 thymine-thymine pyrimidine-pyrimidone photoproduct (6-4PP), but complete lesion bypass is only a fraction of that observed with the CPD. Our data indicate, therefore, that poliota possesses the ability to insert nucleotides opposite UV photoproducts as well as to perform unassisted translesion replication that is likely to be highly mutagenic.

Base Pair Mismatch↗

PubMed1992

Maternal height and age: risk factors for cephalopelvic disproportion in Zimbabwe.

Maternal age and stature are among several factors used to screen pregnant women for potential risk of labour complications. In a population-based case-control study in Harare, Zimbabwe, multivariate analysis was carried out to evaluate the importance of maternal age and height as risk factors for cephalopelvic disproportion (CPD). Using data abstracted from the medical records of 203 women with operative deliveries due to CPD and 299 women with normal unassisted vaginal deliveries, multiple logistic regression models were developed. Although maternal age < 18 years was not a significant risk factor in this study (perhaps because there were few women in this age group), advanced maternal age (> or = 35 years) was associated with a relative risk of 2.7 compared to women 20-34, after adjusting for other demographic and obstetric factors. Maternal height < 160 cm was associated with a twofold increased risk of CPD as compared to taller women.

Adolescent↗

PubMed1983

Peritoneal macrophages and opsonins: antibacterial defense in patients undergoing chronic peritoneal dialysis.

The antibacterial activity of phagocytic cells and opsonins in peritoneal dialysis effluents from 21 patients undergoing chronic peritoneal dialysis (CPD) was studied. Effluents contained an average of 12 x 10(6) cells per liter that were predominantly macrophages. Macrophages phagocytized and killed opsonized Staphylococcus epidermidis, Staphylococcus aureus, and Escherichia coli as efficiently as did polymorphonuclear neutrophils (PMNs) from healthy donors. Macrophage chemiluminescence was one-third of that observed with donor PMNs. In the absence of opsonins, macrophages efficiently phagocytized and killed S. aureus by binding S. aureus cell wall protein A to macrophage surface IgG. Nine (43%) of 21 effluents failed to opsonize S. epidermidis, and none opsonized E. coli. When present, titers of S. epidermidis opsonins were 50- to 100-fold lower than that of normal serum. IgG and C3 concentrations in effluent reflected its opsonic capacity. Macrophages from patients undergoing CPD thus have intact phagocytic and bactericidal functions. However, the low level of opsonic molecules and inadequate numbers of macrophages in the peritoneal cavity may predispose patients undergoing CPD to peritonitis.

Ascitic Fluid↗

PubMed1997

Flavin adenine dinucleotide as a chromophore of the Xenopus (6-4)photolyase.

Two types of enzyme utilizing light from the blue and near-UV spectral range (320-520 nm) are known to have related primary structures: DNA photolyase, which repairs UV-induced DNA damage in a light-dependent manner, and the blue light photoreceptor of plants, which mediates light-dependent regulation of seedling development. Cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts [(6-4)photoproducts] are the two major photoproducts produced in DNA by UV irradiation. Two types of photolyases have been identified, one specific for CPDs (CPD photolyase) and another specific for (6-4)photoproducts [(6-4)photolyase]. (6-4)Photolyase activity was first found in Drosophila melanogaster and to date this gene has been cloned only from this organism. The deduced amino acid sequence of the cloned gene shows that (6-4)photolyase is a member of the CPD photolyase/blue light photoreceptor family. Both CPD photolyase and blue light photoreceptor are flavoproteins and bound flavin adenine dinucleotides (FADs) are essential for their catalytic activity. Here we report isolation of a Xenopus laevis(6-4)photolyase gene and show that the (6-4)photolyase binds non- covalently to stoichiometric amounts of FAD. This is the first indication of FAD as the chromophore of (6-4)photolyase.

Animals↗

PubMed2003

NMR study on the interaction between RPA and DNA decamer containing cis-syn cyclobutane pyrimidine dimer in the presence of XPA: implication for damage verification and strand-specific dual incision in nucleotide excision repair.

In mammalian cells, nucleotide excision repair (NER) is the major pathway for the removal of bulky DNA adducts. Many of the key NER proteins are members of the XP family (XPA, XPB, etc.), which was named on the basis of its association with the disorder xerodoma pigmentosum. Human replication protein A (RPA), the ubiquitous single-stranded DNA-binding protein, is another of the essential proteins for NER. RPA stimulates the interaction of XPA with damaged DNA by forming an RPA-XPA complex on damaged DNA sites. Binding of RPA to the undamaged DNA strand is most important during NER, because XPA, which directs the excision nucleases XPG and XPF, must bind to the damaged strand. In this study, nuclear magnetic resonance (NMR) spectroscopy was used to assess the binding of the tandem high affinity DNA-binding domains, RPA-AB, and of the isolated domain RPA-A, to normal DNA and damaged DNA containing the cyclobutane pyrimidine dimer (CPD) lesion. Both RPA-A and RPA-AB were found to bind non- specifically to both strands of normal and CPD- containing DNA duplexes. There were no differences observed when binding to normal DNA duplex was examined in the presence of the minimal DNA-binding domain of XPA (XPA-MBD). However, there is a drastic difference for CPD-damaged DNA duplex as both RPA-A and RPA-AB bind specifically to the undamaged strand. The strand-specific binding of RPA and XPA to the damaged duplex DNA shows that RPA and XPA play crucial roles in damage verification and guiding cleavage of damaged DNA during NER.

DNA↗